EP3684782A1 - Substituierte nukleoside, nukleotide und analoga davon - Google Patents

Substituierte nukleoside, nukleotide und analoga davon

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Publication number
EP3684782A1
EP3684782A1 EP18783113.6A EP18783113A EP3684782A1 EP 3684782 A1 EP3684782 A1 EP 3684782A1 EP 18783113 A EP18783113 A EP 18783113A EP 3684782 A1 EP3684782 A1 EP 3684782A1
Authority
EP
European Patent Office
Prior art keywords
compound
optionally substituted
alkyl
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP18783113.6A
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English (en)
French (fr)
Inventor
Leonid Beigelman
Jerome Deval
Marija Prhavc
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Biopharma Inc
Original Assignee
Janssen Biopharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Biopharma Inc filed Critical Janssen Biopharma Inc
Publication of EP3684782A1 publication Critical patent/EP3684782A1/de
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/06—Heterocyclic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals

Definitions

  • the present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are nucleotide analogs, pharmaceutical compositions that include one or more nucleotide analogs and methods of synthesizing the same. Also disclosed herein are methods of treating viral diseases and/or conditions with a nucleotide analog, alone or in combination therapy with one or more other agents.
  • Nucleoside analogs are a class of compounds that have been shown to exert antiviral and anticancer activity both in vitro and in vivo, and thus, have been the subject of widespread research for the treatment of viral infections.
  • Nucleoside analogs are usually therapeutically inactive compounds that are converted by host or viral enzymes to their respective active anti-metabolites, which, in turn, may inhibit polymerases involved in viral or cell proliferation. The activation occurs by a variety of mechanisms, such as the addition of one or more phosphate groups and, or in combination with, other metabolic processes.
  • viruses are grouped by their shared properties according to four main characteristics: (1) nucleic acid (DNA or RNA); (2) symmetry of capsid (icosahedral, helical or complex); (3) naked or enveloped; and (4) genome architecture (positive sense or negative sense, and single stranded or double stranded).
  • viruses are grouped according to both their genome structure and method of replication: Group 1 (double-stranded DNA virus); Group II: (single stranded DNA virus); Group III (double-stranded RNA virus); Group IV (single stranded positive sense RNA virus); Group V (single stranded negative sense RNA virus); Group VI (single stranded positive sense RNA virus that replicates through a DNA intermediate); and Group VII (double stranded DNA virus that replicates through a single stranded RNA intermediate).
  • Group 1 double-stranded DNA virus
  • Group II single-stranded DNA virus
  • Group III double-stranded RNA virus
  • Group IV single stranded positive sense RNA virus
  • Group V single stranded negative sense RNA virus
  • Group VI single stranded positive sense RNA virus that replicates through a DNA intermediate
  • Group VII double stranded DNA virus that replicates through a single stranded RNA intermediate.
  • viruses within the Picornaviridae, Flaviviridae, Filoviridae, Pneumoviridae and Coronaviridae families have diverse characteristics that make it very challenging to develop an antiviral that is active against viruses in two or more of the families.
  • the viruses within the Picornaviridae family are non-enveloped, positive sense, single-stranded, spherical RNA viruses with an icosahedral capsid. They are Group IV viruses under the Baltimore classification, in the order Picornavirales.
  • the Picornavirus genomes are approximately 7-8 kilobases long and have an IRES (Internal Ribosomal Entry Site). These viruses are polyadenylated at the 3' end, and has a VPg protein at the 5' end in place of a cap.
  • Genera within the Picornaviridae family include Aphthovirus, Aquamavirus, Avihepatovirus, Cardiovirus, Cosavirus, Dicipivirus, Enterovirus, Erbovirus, Hepatovirus, Kobuvirus, Megrivirus, Parechovirus, Rhinovirus, Salivirus, Sapelovirus, Senecavirus, Teschovirus and Tremovirus.
  • Enteroviruses are transmitted through the fecal-oral route and/or via aerosols of respiratory droplets, and are highly communicable.
  • the genus of Enterovirus includes several species, including: enterovirus A, enterovirus B, enterovirus C, enterovirus D, enterovirus E, enterovirus F, enterovirus G, enterovirus Henterovirus J, rhinovirus A, rhinovirus B and rhinovirus C.
  • enteroviruses Within a species of the aforementioned enteroviruses are the following serotypes: polioviruses, rhino viruses, coxsackieviruses, echo viruses and enterovirus.
  • Rhinoviruses are the cause of the common cold. Rhinoviruses are named because of their transmission through the respiratory route and replication in the nose. A person can be infected with numerous rhinoviruses over their lifetime because immunity develops for each serotype. Thus, each serotype can cause a new infection.
  • a hepatitis A infection is the result of an infection with a Hepatitis A virus.
  • Hepatovirus is transmitted through the fecal-oral route. Transmission can occur via person-to-person by ingestion of contaminated food or water, or through direct contact with an infectious person.
  • Parechovirus include human parechovirus 1 (echovirus 22), human par echo virus 2 (echovirus 23), human parechovirus 3, human parechovirus 4, human parechovirus 5 and human parechovirus 6.
  • the viruses with the Flaviviridae family are enveloped, positive sense, single-stranded, spherical RNA viruses with an icosahedral shaped capsid. They are Group IV viruses under the Baltimore classification, and have not been assigned to an order. These viruses are polyadenylated at the 5' end but lack a 3'polyadenylate tail. Genera within the Flaviviridae family include: Flavivirus, Pestivirus and Hepacivirus. Flaviviridae viruses are predominantly arthropod-borne, and are often transmitted via mosquitos and ticks.
  • Effects/symptoms of a Picornaviridae viral infection depend on the species of virus, and can include, but are not limited to, fever, blisters, rash, meningitis, conjunctivitis, acute hemorrhagic conjunctivitis (AHC), sore throat, nasal congestion, runny nose, sneezing, coughing, loss of appetite, muscle aches, headache, fatigue, nausea, jaundice, encephalitis, herpangina, myocarditis, pericarditis, meningitis, Bornholm disease, myalgia, nasal congestion, muscle weakness, loss of appetite, fever, vomiting, abdominal pain, abdominal discomfort, dark urine and muscle pain.
  • AHC acute hemorrhagic conjunctivitis
  • Hepaciviruses include Hepatitis C (HCV). There are various nonstructural proteins of HCV, such as NS2, NS3, NS4, NS4A, NS4B, NS5A and NS5B. NS5B is believed to be an RNA-dependent RNA polymerase involved in the replication of HCV RNA. Flaviviruses include several encephalitis viruses (for example, Japanese Encephalitis virus (JEV), St. Louis encephalitis virus (SLEV) and tick-borne encephalitis virus (TBEV)), dengue virus 1-4 (DENV), West Nile virus (WNV), yellow fever virus (YFV), and Zika virus (ZIKV).
  • JEV Japanese Encephalitis virus
  • SLEV St. Louis encephalitis virus
  • TBEV tick-borne encephalitis virus
  • DEV dengue virus 1-4
  • WNV West Nile virus
  • YFV yellow fever virus
  • ZIKV Zika virus
  • a West Nile infection can lead to West Nile fever or severe West Nile disease (also called West Nile encephalitis or meningitis or West Nile poliomyelitis).
  • Symptoms of West Nile fever include fever, headache, tiredness, body aches, nausea, vomiting, a skin rash (on the trunk of the body) and swollen lymph glands.
  • Symptoms of West Nile disease include headache, high fever, neck stiffness, stupor, disorientation, coma, tremors, convulsions, muscle weakness and paralysis.
  • Current treatment for a West Nile virus infection is supportive, and no vaccination is currently available for humans.
  • Yellow fever is an acute viral hemorrhagic disease. As provided by the WHO, up to 50% of severely affected persons without treatment die from yellow fever. An estimated 200,000 cases of yellow fever, causing 30,000 deaths, worldwide occur each year. As with other Flaviviruses, there is no cure or specific treatment for yellow fever, and treatment with ribavirin and interferons are insufficient. Symptoms of a yellow fever infection include fever, muscle pain with prominent backache, headache, shivers, loss of appetite, nausea, vomiting, jaundice and bleeding (for example from the mouth, nose, eyes and/or stomach). Viruses within the Pestivirus genus include bovine viral diarrhea 1, bovine viral diarrhea 2, and classic swine fever virus.
  • Viral encephalitis causes inflammation of the brain and/or meninges. Symptoms include high fever, headache, sensitivity to light, stiff neck and back, vomiting, confusion, seizures, paralysis and coma. There is no specific treatment for an encephalitis infection, such as Japanese encephalitis, St. Louis encephalitis and tick borne encephalitis. According to the Centers for Disease Control, Zika is spread mostly by the bite of an infected Aedes species mosquito (Ae. aegypti and Ae. albopictus) and can be passed from a pregnant woman to her fetus. Infection during pregnancy can cause certain birth defects. Many people infected with Zika virus will not have symptoms or will only have mild symptoms.
  • Zika Zika fever, rash, joint pain, and conjunctivitis. Zika is usually mild with symptoms lasting for several days to a week. People usually do not get sick enough to go to the hospital, and they very rarely die of Zika. For this reason, many people might not realize they have been infected. Symptoms of Zika are similar to other viruses spread through mosquito bites, like dengue and chikungunya.
  • the viruses of the Filoviridae family are enveloped, negative sense, single-stranded, linear RNA viruses. They are Group V viruses under the Baltimore classification, in the order Mononegavirales. Three genera within the Filoviridae family are Ebolavirus, Marburgvirus and "Cuevavirus" (tentative). The five recognized species of Ebolavirus are Ebola virus (EBOV), Reston ebolavirus (REBOV), Sudan ebolavirus (SEBOV), Tai Forest ebolavirus (TAFV) and Bundibugyo ebolavirus (BEBOV). The two recognized species of Marburgvirus are Marburg virus (MARV) and Ravn virus (RAW). Ebolavirus and Marburgvirus are highly infectious and contagious.
  • Ebolavirus and Marburgvirus are highly infectious and contagious.
  • Ebolavirus and Marburgvirus can also be transmitted by handling sick or dead infected wild animals.
  • Ebola hemorrhagic fever (EHF) is caused by an Ebolavirus infection.
  • Marburg virus disease (MVD) is a human disease caused by a Marburgvirus, and causes Marburgvirus hemorrhagic fever (MHF).
  • Ebolavirus and Marburgvirus cause viral hemorrhagic fever in various primates, including humans.
  • Pneumoviridae is a relatively new virus family that was created by elevating the paramyxoviral subfamily Pneumovirinae.
  • the viruses of the Pneumoviridae family are negative sense, single-stranded, RNA viruses. They are Group V viruses under the Baltimore classification, in the order Mononegavirales.
  • Two genera within the Pneumoviridae family are Metapneumo virus and Orthopneumovirus.
  • the two recognized species of Metapneumovirus are avian metapneumovirus (AMPV) and human metapneumovirus (HMPV).
  • BRSV Bovine respiratory syncytial virus
  • HRSV Human respiratory syncytial virus
  • MPV Murine pneumonia virus
  • Viruses in the Pneumoviridae family are typically transmitted through respiratory secretions and are often associated with respiratory infections.
  • Coronaviridae viruses are a family of enveloped, positive-stranded, single-stranded, spherical RNA viruses. They are Group IV viruses under the Baltimore classification, in the order Nidovirales. Coronaviruses are named for the crown-like spikes on their surface. The Coronaviridae family includes two sub-families, Coronavirus and Torovirus.
  • Coronavirus genus has a helical nucleocapsid
  • Torovirus genus has a tubular nucleocapsid.
  • Coronavirus sub-family Within the Coronavirus sub-family are the following genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus.
  • Genera within the Torovirus sub-family are Bafinivirus and Torovirus.
  • Human coronaviruses usually cause mild to moderate upper-respiratory tract illnesses, like the common cold, that last for a short amount of time (although some coronaviruses can be deadly). Symptoms may include runny nose, cough, sore throat, and fever. These viruses can sometimes cause lower-respiratory tract illnesses, such as pneumonia. This is more common in people with cardiopulmonary disease or compromised immune systems, or the elderly.
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • Betacoronavirus genus a member of the Betacoronavirus genus, and causes Middle East Respiratory Syndrome (MERS).
  • MERS is an acute respiratory illness. About half of the individuals confirmed to have been infected with MERS died. There is no current treatment or vaccine for MERS.
  • SARS-CoV SARS coronavirus
  • SARS-CoV is the virus that causes severe acute respiratory syndrome (SARS).
  • SARS was first reported in Asia in February 2003.
  • SARS is an airborne virus, and can spread by the inhalation of small droplets of water that an infected individuals releases into the air (for example, by coughing and/or sneezing), touching a contaminated surface and/or by being in close proximity of an infected individual (for example, cared for or lived with a person known to have SARS or having a high likelihood of direct contact with respiratory secretions and/or body fluids of a patient known to have SARS, including kissing or embracing, sharing eating or drinking utensils, close conversation (within 3 feet), physical examination, and any other direct physical contact between people).
  • the two genera within the Togaviridae family are Alphavirus and Rubivirus. Viruses within this family are enveloped, positive-sense, single-stranded, linear RNA viruses. To date, Rubivirus has one species, Rubella virus. Viruses classified in the Alphavirus genus include Venezuelan equine encephalitis (VEE) viruses. VEE viruses are mainly transmitted by mosquitos and cause Venezuelan equine encephalitis and encephalomyelitis. The VEE complex of viruses includes six antigenic subtypes (I-VI) divided by antigenic variants. Additionally, VEE viruses are divided into two groups, epizootic (or epidemic) and enzootic (or endemic).
  • VEE Venezuelan equine encephalitis
  • subtype I Venezuelan equine encephalomyelitis virus (VEEV), is divided into five antigenic variants (variants AB-F).
  • Subtype II is known as Everglades virus, subtype III as Mucambo virus, and subtype IV as Pixuna virus. Equine species along with humans can be infected with VEE viruses. Currently, there is no vaccine available for horses or humans.
  • Chikungunya is an arthropod-borne virus and can be transmitted to humans by mosquitoes (such as Aedes mosquitos).
  • mosquitoes such as Aedes mosquitos.
  • Alphaviruses are Barmah Forest virus, Mayaro virus (MAYV), O'nyong'nyong virus, Ross River virus (RRV), Semliki Forest virus, Sindbis virus (SINV), Una virus, Eastern equine encephalitis virus (EEE) and Western equine encephalomyelitis (WEE). These Alphaviruses are mainly arthropod-borne, and transmitted via mosquitos.
  • panviral activity is generally considered to be desirable, the activity of such compounds against diverse viruses also raises the prospect that increased off-target effects might also be observed, leading to potential toxicity concerns that tend to slow clinical development.
  • panviral nucleoside analogs and particularly those having low toxicity.
  • Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) and/or pharmaceutically acceptable salts thereof exhibit panviral activity. Such panviral activity is surprising because of the diversity of viruses against which they are active.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof exhibits activity against viruses that are in two or more different virus families.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof exhibits activity against a virus in two of more of the Picornaviridae, Flaviviridae, Filoviridae, Pneumoviridae and/or Coronaviridae families.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof has low toxicity. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, has both low toxicity and is panviral, unexpectedly exhibiting activity against viruses that are in two or more different virus families despite its low toxicity.
  • Some embodiments disclosed herein relate to a method of ameliorating and/or treating a Picornaviridae viral infection that can include administering to a subject identified as suffering from the Picornaviridae viral infection an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a Picornaviridae viral infection.
  • Still other embodiments described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a Picornaviridae viral infection.
  • Some embodiments disclosed herein relate to a method of ameliorating and/or treating a Picornaviridae viral infection that can include contacting a cell infected with the picornavirus with an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
  • inventions described herein relate to using one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating and/or treating a Picornaviridae viral infection that can include contacting a cell infected with the picornavirus with an effective amount of said compound(s).
  • a compound of Formula (I) for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Still other embodiments described herein relate to one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a Picornaviridae viral infection by contacting a cell infected with the picornavirus with an effective amount of said compound(s).
  • compounds described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a Picornaviridae viral infection by contacting a cell infected with the picornavirus with an effective amount of said compound(s).
  • Some embodiments disclosed herein relate to a method of inhibiting replication of a Picornaviridae virus that can include contacting a cell infected with the picornavirus with an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
  • Other embodiments described herein relate to using one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a Picornaviridae virus that can include contacting a cell infected with the Picornaviridae virus with an effective amount of said compound(s).
  • Still other embodiments described herein relate to one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof, that can be used for inhibiting replication of a Picornaviridae virus by contacting a cell infected with the picornavirus with an effective amount of said compound(s).
  • the Picornaviridae virus can be selected from a rhinovirus, hepatitis A virus, a coxasackie virus and an enterovirus.
  • Some embodiments disclosed herein relate to a method of ameliorating and/or treating a Flaviviridae viral infection that can include administering to a subject identified as suffering from the Flaviviridae viral infection an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof.
  • inventions disclosed herein relate to a method of ameliorating and/or treating a Flaviviridae viral infection that can include contacting a cell infected with the Flaviviridae virus with an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Still other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a Flaviviridae viral infection.
  • compounds described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Still other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a Flaviviridae viral infection.
  • Yet still other embodiments described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a Flaviviridae viral infection.
  • Some embodiments disclosed herein relate to a method of inhibiting replication of a Flaviviridae virus that can include contacting a cell infected with the Flaviviridae with an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
  • Flaviviridae virus can be selected from Hepatitis C (HCV), dengue and Zika.
  • Some embodiments disclosed herein relate to a method of ameliorating and/or treating a Filoviridae viral infection that can include administering to a subject identified as suffering from the Filoviridae viral infection an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof.
  • inventions disclosed herein relate to a method of ameliorating and/or treating a Filoviridae viral infection that can include contacting a cell infected with the Filoviridae virus with an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Still other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a Filoviridae viral infection.
  • compounds described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
  • Still other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a Filovirida
  • inventions described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a Filoviridae viral infection.
  • Some embodiments disclosed herein relate to a method of inhibiting replication of a Filoviridae virus that can include contacting a cell infected with the Filoviridae with an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
  • inventions described herein relate to using one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a Filoviridae virus. Still other embodiments described herein relate to one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof, that can be used for inhibiting replication of a Filoviridae virus.
  • the Filoviridae virus can be an Ebolavirus or a Marburgvirus.
  • Some embodiments disclosed herein relate to a method of ameliorating and/or treating a Pneumoviridae viral infection that can include administering to a subject identified as suffering from the Pneumoviridae viral infection an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof.
  • inventions disclosed herein relate to a method of ameliorating and/or treating a Pneumoviridae viral infection that can include contacting a cell infected with the Pneumoviridae virus with an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Still other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a Pneumoviridae viral infection.
  • compounds described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
  • Still other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating
  • inventions described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a Pneumoviridae viral infection.
  • Some embodiments disclosed herein relate to a method of inhibiting replication of a Pneumoviridae virus that can include contacting a cell infected with the Pneumoviridae with an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
  • inventions described herein relate to using one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a Pneumoviridae virus. Still other embodiments described herein relate to one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof, that can be used for inhibiting replication of a Pneumoviridae virus.
  • the Pneumoviridae virus can be a human respiratory syncytial virus.
  • Some embodiments disclosed herein relate to a method of ameliorating and/or treating a Coronaviridae viral infection that can include administering to a subject identified as suffering from the Coronaviridae viral infection an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof.
  • inventions disclosed herein relate to a method of ameliorating and/or treating a Coronaviridae viral infection that can include contacting a cell infected with the Coronaviridae virus with an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Still other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a Coronaviridae viral infection.
  • compounds described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
  • Still other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a Coronavirida
  • inventions described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a Coronaviridae viral infection.
  • Some embodiments disclosed herein relate to a method of inhibiting replication of a Coronaviridae virus that can include contacting a cell infected with the Coronaviridae with an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
  • FIG. 1 For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • FIG. 1 For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • FIG. 1 For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • FIG. 1 For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • FIG. 1 For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • FIG. 1 the Coronaviridae virus can be a human a- coronavirus viral infection or a human ⁇ -coronavirus viral infection.
  • Figure 1 illustrates a reaction scheme for making compound 1.
  • Figure 2 illustrates a reaction scheme for making compound 2.
  • Figure 3 illustrates a reaction scheme for making compound 3.
  • Figure 4 illustrates a reaction scheme for making compound 4.
  • Figure 5 illustrates a reaction scheme for making compound 5.
  • Figure 6 illustrates a reaction scheme for making compound 6.
  • Figure 7 illustrates a reaction scheme for making compound 7.
  • Figure 8 illustrates a reaction scheme for making compound 8.
  • any "R" group(s) such as, without limitation, R A , R 1A ,
  • R group may be substituted or unsubstituted. If two "R" groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R a and R of an NR a R group are indicated to be “taken together,” it means that they are covalently bonded to one another to form a ring:
  • R groups are not limited to the variables or substituents defined previously.
  • substituent(s) may be selected from one or more of the indicated substituents.
  • the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl,
  • C a to Cb in which "a" and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to "b", inclusive, carbon atoms.
  • a "Ci to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH3CH2-, CH3CH2CH2-, (CH 3 ) 2 CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-. If no "a” and "b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest range described in these definitions is to be assumed.
  • an asterisk used with respect to a chemical group indicates a point of attachment.
  • the asterisk in the chemical group "*- (CR 15A R 16A ) P -0-Ci-2 4 alkyl” indicates the point of attachment for that chemical group to another group or molecule.
  • alkyl refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • the alkyl group of the compounds may be designated as "C1-C4 alkyl” or similar designations.
  • C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl.
  • the alkyl group may be substituted or unsubstituted.
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • An alkenyl group may be unsubstituted or substituted.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • An alkynyl group may be unsubstituted or substituted.
  • cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • cycloalkenyl refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi- electron system throughout all the rings (otherwise the group would be "aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion.
  • a cycloalkenyl can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s).
  • a cycloalkenyl group may be unsubstituted or substituted.
  • aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
  • the number of carbon atoms in an aryl group can vary.
  • the aryl group can be a C 6 -Ci4 aryl group, a C6-C10 aryl group, or a Ce aryl group.
  • aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • An aryl group may be substituted or unsubstituted.
  • heteroaryl refers to a monocyclic, bicyclic and tricyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1 to 5 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • the number of atoms in the ring(s) of a heteroaryl group can vary.
  • the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
  • heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond.
  • heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1 ,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyr
  • heterocyclyl or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
  • a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
  • the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen.
  • a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heteroalicyclic may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted.
  • heterocyclyl or “heteroalicyclyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4- dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3- oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1 ,4-oxathiane, tetrahydro-l,4-thiazine, 2H-1,2- oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-l,3,5-triazine, imidazoline, imidazolidine, isoxazoline,
  • aralkyl and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and aryl group of an aryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl) and naphthyl(alkyl).
  • heteroarylkyl and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl) and their benzo-fused analogs.
  • heteroalicyclyl(alkyl) and “heterocyclyl(alkyl)” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heterocyclyl of a heteroalicyclyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl) and 1,3- thiazinan-4-yl(methyl).
  • Lower alkylene groups are straight-chained -CH2- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-) and butylene (-CH2CH2CH2CH2-).
  • a lower alkylene group can be substituted by replacing one or more hydrogen or deuterium of the lower alkylene group with a substituent(s) listed under the definition of "substituted.”
  • alkoxy refers to the formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl is defined herein.
  • R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl is defined herein.
  • a non-limiting list of alkoxys is methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,
  • acyl refers to a hydrogen, deuterium, alkyl, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.
  • hydroxyalkyl refers to an alkyl group in which one or more of the hydrogen or deuterium atoms are replaced by a hydroxy group.
  • exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxy ethyl, 3-hydroxypropyl, 2- hydroxypropyl and 2,2-dihydroxyethyl.
  • a hydroxyalkyl may be substituted or unsubstituted.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen or deuterium atoms are replaced by a halogen (e.g., mono-haloalkyl, di- haloalkyl and tri-haloalkyl).
  • a halogen e.g., mono-haloalkyl, di- haloalkyl and tri-haloalkyl.
  • groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -chloro-2-fluoromethyl and 2-fluoroisobutyl.
  • a haloalkyl may be substituted or unsubstituted.
  • haloalkoxy refers to an -O-alkyl group in which one or more of the hydrogen or deuterium atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy).
  • a halogen e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy.
  • Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, l-chloro-2- fluoromethoxy and 2-fluoroisobutoxy.
  • a haloalkoxy may be substituted or unsubstituted.
  • a “sulfenyl” group refers to an "-SR" group in which R can be hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
  • a sulfenyl may be substituted or unsubstituted.
  • a “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl.
  • a sulfonyl may be substituted or unsubstituted.
  • An O- carboxy may be substituted or unsubstituted.
  • An ester and C-carboxy may be substituted or unsubstituted.
  • a thiocarbonyl may be substituted or unsubstituted.
  • a "trihalomethanesulfonyl” group refers to an "X3CSO2-" group wherein each X is a halogen.
  • a "trihalomethanesulfonamido” group refers to an "X3CS(0)2N(RA)-" group wherein each X is a halogen, and RA is hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or
  • amino refers to a -NH2 group.
  • hydroxy refers to a -OH group.
  • a "cyano" group refers to a "-CN” group.
  • An "isocyanato” group refers to a "-NCO” group.
  • a "thiocyanato" group refers to a "-CNS” group.
  • An "isothiocyanato" group refers to an " -NCS” group.
  • a “mercapto” group refers to an "-SH” group.
  • S-sulfonamido refers to a "-S02N(RARB)" group in which RA and RB can be independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
  • An S-sulfonamido may be substituted or unsubstituted.
  • N-sulfonamido refers to a "RSC N(RA)-" group in which R and RA can be independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
  • R and RA can be independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
  • An N-sulfonamido may be substituted or unsubstituted.
  • An O-carbamyl may be substituted or unsubstituted.
  • R and RA can be independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
  • An N-carbamyl may be substituted or unsubstituted.
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • R and RA can be independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
  • An N-thiocarbamyl may be substituted or unsubstituted.
  • a C-amido may be substituted or unsubstituted.
  • R and RA can be independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
  • An N-amido may be substituted or unsubstituted.
  • halogen atom or "halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
  • substituents there may be one or more substituents present.
  • haloalkyl may include one or more of the same or different halogens.
  • C1-C3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
  • nucleoside is used herein in its ordinary sense as understood by those skilled in the art, and refers to a compound composed of an optionally substituted pentose moiety or modified pentose moiety attached to a heterocyclic base or tautomer thereof via a N-glycosidic bond, such as attached via the 9-position of a purine-base or the 1- position of a pyrimidine-base.
  • examples include, but are not limited to, a ribonucleoside comprising a ribose moiety and a deoxyribonucleoside comprising a deoxyribose moiety.
  • a modified pentose moiety is a pentose moiety in which an oxygen atom has been replaced with a carbon and/or a carbon has been replaced with a sulfur or an oxygen atom.
  • a "nucleoside” is a monomer that can have a substituted base and/or sugar moiety. Additionally, a nucleoside can be incorporated into larger DNA and/or RNA polymers and oligomers. In some instances, the nucleoside can be a nucleoside analog drug.
  • nucleotide is used herein in its ordinary sense as understood by those skilled in the art, and refers to a nucleoside having a phosphate ester bound to the pentose moiety, for example, at the 5 '-position.
  • heterocyclic base refers to an optionally substituted nitrogen-containing heterocyclyl that can be attached to an optionally substituted pentose moiety or modified pentose moiety.
  • the heterocyclic base can be selected from an optionally substituted purine-base, an optionally substituted pyrimidine- base and an optionally substituted triazole-base (for example, a 1,2,4-triazole).
  • purine-base is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers.
  • pyrimidine-base is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers.
  • a non- limiting list of optionally substituted purine-bases includes purine, adenine, guanine, hypoxanthine, xanthine, alloxanthine, 7-alkylguanine (e.g. 7-methylguanine), theobromine, caffeine, uric acid and isoguanine.
  • pyrimidine-bases include, but are not limited to, cytosine, thymine, uracil, 5,6-dihydrouracil and 5-alkylcytosine (e.g., 5-methylcytosine).
  • An example of an optionally substituted triazole-base is l ,2,4-triazole-3-carboxamide.
  • heterocyclic bases include diaminopurine, 8-oxo-N 6 -alkyladenine (e.g., 8-oxo-N 6 -methyladenine), 7-deazaxanthine, 7-deazaguanine, 7-deazaadenine, N 4 ,N 4 - ethanocytosin, N 6 ,N 6 -ethano-2,6-diaminopurine, 5-halouracil (e.g., 5-fluorouracil and 5- bromouracil), pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic bases described in U.S. Patent Nos.
  • 8-oxo-N 6 -alkyladenine e.g., 8-oxo-N 6 -methyladenine
  • 7-deazaxanthine 7-deazaguanine
  • 7-deazaadenine 7-deazaadenine
  • a heterocyclic base can be optionally substituted with an amine or an enol protecting group(s).
  • N-linked amino acid refers to an amino acid that is attached to the indicated moiety via a main-chain amino or mono-substituted amino group.
  • amino acid is attached in an -N-linked amino acid, one of the hydrogen or deuteriums that is part of the main-chain amino or mono-substituted amino group is not present and the amino acid is attached via the nitrogen.
  • N-linked amino acids can be substituted or unsubstituted.
  • ester derivative refers to an amino acid in which a main-chain carboxylic acid group has been converted to an ester group.
  • N-linked amino acid ester derivatives can be substituted and un
  • -O-linked amino acid refers to an amino acid that is attached to the indicated moiety via the hydroxy from its main-chain carboxylic acid group.
  • the amino acid is attached in an -O-linked amino acid, the hydrogen or deuterium that is part of the hydroxy from its main-chain carboxylic acid group is not present and the amino acid is attached via the oxygen.
  • O-linked amino acids can be substituted or unsubstituted.
  • amino acid refers to any amino acid (both standard and non-standard amino acids), including, but not limited to, a-amino acids, ⁇ - amino acids, ⁇ -amino acids and ⁇ -amino acids.
  • suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.
  • suitable amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine.
  • phosphate is used in its ordinary sense as understood by those skilled in the art, and includes its protonated forms (for example, as used herein, the terms "monophosphate,”
  • diphosphate and triphosphate are used in their ordinary sense as understood by those skilled in the art, and include protonated forms.
  • protecting group and “protecting groups” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unwanted chemical reactions.
  • Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J.F.W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups.
  • the protecting group moiety may be chosen in such a way, that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art.
  • a non-limiting list of protecting groups include benzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g., t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g.
  • methoxymethyl ether substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, tri-iso- propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy] methyl or t-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclic ketal (e.g.
  • cyclic ketals e.g., 1,3-dioxane, 1,3-dioxolanes and those described herein
  • acyclic acetal e.g., those described herein
  • acyclic hemiacetal e.g., 1,3-dithiane or 1,3- dithiolane
  • orthoesters e.g., those described herein
  • triarylmethyl groups e.g., trityl; monomethoxytrityl (MMTr); 4,4'-dimethoxytrityl (DMTr); 4,4',4"-trimethoxytrityl (TMTr); and those described herein).
  • salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid.
  • compositions can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid.
  • organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine
  • the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
  • a group of items linked with the conjunction 'and' should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or' unless expressly stated otherwise.
  • a group of items linked with the conjunction 'or' should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or' unless expressly stated otherwise.
  • each center may be independently of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
  • each double bond may be independently E or Z, or a mixture thereof.
  • phosphorothioate include the following: and .
  • all tautomers of heterocyclic bases known in the art are intended to be included, including tautomers of natural and non-natural purine-bases and pyrimidine-bases.
  • valencies are to be filled as needed with hydrogen (also referred to as protium, hydrogen- 1 or 3 ⁇ 4) or isotopes thereof.
  • a suitable isotope of hydrogen is deuterium (also referred to as hydrogen-2 or 2 H).
  • the compounds, methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like.
  • the compounds described herein exist in unsolvated form.
  • Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms.
  • R can selected from the group consisting of fluoro, cyano, azido, an unsubstituted C2-4 alkenyl, unsubstituted C2-4 alkynyl, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 alkyl, and a substituted C1-4 alkyl.
  • the unsubstituted C1-4 alkoxy is methoxy.
  • the unsubstituted C1-4 alkyl is methyl.
  • R 1A when R 1A is a substituted C1-4 alkyl, it is substituted with one or more substituents selected from fluoro and chloro.
  • R 1A can be a substituted C1-4 alkyl that is selected from the group consisting of -(CH2)i-4Cl, -(CH2)i-4F, and -CHF2.
  • substituted C1-4 alkyl thus include chloromethyl, fluoromethyl and difluoromethyl.
  • R 1A can be cyano.
  • the following Formulae (Ial) is an example of embodiments of compounds of the Formula (I) in which the variable R 1A is cyano and the variables R 2A , R 3A , R 4A , R 5A , R al and R a2 are as described elsewhere herein.
  • R 4A can be selected from the group consisting of fluoro, cyano, azido, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 alkyl, and a substituted C1-4 alkyl, wherein said substituted C1-4 alkyl is substituted with one or more substituents selected from fluoro and chloro.
  • R 4A is selected from the group consisting of fluoro, cyano, azido, and an unsubstituted Ci-4 alkyl.
  • R 4A is selected from the group consisting of fluoro, cyano, azido, and Ci-4 alkyl substituted with one or more substituents selected from fluoro and chloro.
  • R 4A is fluoro.
  • R 4A is cyano.
  • R 4A is azido.
  • R 4A is an unsubstituted Ci-4 alkyl.
  • R 4A is methyl.
  • R 4A can be a substituted C1-4 alkyl that is selected from the group consisting of -(CH2)i-4Cl, -(CH2)i-4F and -CHF2.
  • substituted C1-4 alkyl thus include chloromethyl, fluoromethyl and difluoromethyl.
  • the substituted C1-4 alkyl is chloromethyl.
  • the substituted C1-4 alkyl is fluoromethyl.
  • the variables R 2A and R 3A of the formula (I) are each independently hydrogen or deuterium. In an embodiment, R 2A and R 3A are both hydrogen. In an embodiment, R 2A and R 3A are both deuterium. In an embodiment, one of R 2A and R 3A is hydrogen and the other is deuterium.
  • the variables R al and R a2 of the formula (I) are each independently hydrogen or deuterium. In an embodiment, R al and R a2 are both hydrogen. In an embodiment, R al and R a2 are both deuterium. In an embodiment, one of R al and R a2 is hydrogen and the other is deuterium.
  • R 1A is selected from the group consisting of fluoro, cyano, azido, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 alkyl, and a substituted C1-4 alkyl
  • R 4A is selected from the group consisting of fluoro, cyano, azido, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 alkyl, and a substituted C1-4 alkyl, wherein said substituted C1-4 alkyl is substituted with one or more substituents selected from fluoro and chloro.
  • R 1A is cyano
  • R 4A is selected from the group consisting of fluoro, cyano, azido, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, chloromethyl, fluoromethyl, and difluoromethyl.
  • R 1A is cyano
  • R 4A is fluoro.
  • R 1A is cyano
  • R 4A is fluoromethyl.
  • R 1A is cyano, and R is chloromethyl.
  • R is cyano, and R is azido.
  • both R 1A and R 4A are cyano.
  • variable R 5A of the Formula (I) is selected from the group consisting of hydrogen, an optionally substituted acyl, an optionally
  • R 8A can be independently selected from absent, hydrogen, an optionally substituted Ci-24 alkyl, an optionally substituted C3-24 alkenyl, an optionally substituted C3-24 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aryl(Ci-6 alkyl), an optionally substituted *-(CR 15A R 16A ) P -0-Ci-24 alkyl, an optionally
  • R can be and
  • R can be absent or hydrogen.
  • R and R can be taken together to form a moiety selected from an optionally substituted and an optionally substituted wherein the oxygens connected to R bA and R /A , the phosphorus and the moiety form a six-membered to ten-membered ring system.
  • R 9A can be independently selected from an optionally substituted Ci-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C3-6 cycloalkenyl, NR 30A R 31A , an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative.
  • the amino acid portion (of the optionally substituted N-linked amino acid and the optionally substituted N-linked amino acid ester derivative) can have various stereochemical configurations.
  • the amino acid portion can be racemic, an L-stereoisomer, a D-stereoisomer or a mixture of L- and D-stereoisomers that is enriched in one or the other of the stereoisomers.
  • the L-stereoisomer content of the amino acid portion is at least about 90%, at least about 95%, or at least about 99%, by weight based on the mixture of L- and D- stereoisomers.
  • R 10A and R 11A can be independently an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;
  • R 12A , R 13A and R 14A can be independently absent or hydrogen;
  • each R 15A , each R 16A , each R 17A and each R 18A can be independently hydrogen, an optionally substituted Ci-24 alkyl or alkoxy;
  • R 19A , R 20A , R 22A and R 23A can be independently selected from hydrogen, an optionally substituted Ci-24 alkyl and an optionally substituted aryl;
  • R 21A and R 24A can be independently selected from hydrogen, an optionally substituted Ci-24 alkyl, an optionally substituted aryl, an optionally substituted -O-Ci-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl, an optionally substituted -O-monocyclic
  • heterocyclyl and and R can be independently selected from hydrogen, an optionally substituted Ci-24 alkyl and an optionally substituted aryl;
  • R and R 27A can be independently -C ⁇ N or an optionally substituted substituent selected from C2-8 organylcarbonyl, C2-8 alkoxycarbonyl and C2-8 organylaminocarbonyl;
  • R 28A can be selected from hydrogen, an optionally substituted Ci-24-alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and an optionally substituted C3-6 cycloalkenyl;
  • R 30A and R 31A can be independently selected from hydrogen, an optionally substituted Ci-24-alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and an optionally substituted C3-6 cycloalkenyl;
  • R 5A can be In some embodiments,
  • R 6A and R 7A can be both hydrogen. In other embodiments, R 6A and R 7A can be both absent. In still other embodiments, at least one R 6A and R 7A can be absent. In yet still other embodiments, at least one R 6A and R 7A can be hydrogen. Those skilled in the art understand that when R 6A and/or R 7A are absent, the associated oxygen(s) will have a negative charge. For example, when R 6A is absent, the oxygen associated with R 6A will have a negative charge. In some embodiments, Z 1A can be O (oxygen). In other embodiments, Z 1A can be S (sulfur). In some embodiments, R 5A can be a monophosphate. In other embodiments, R 5A can be a monothiophosphate.
  • R 5A when R 5A is one of R 6A and R 7A can be hydrogen, and the other of R 6A and R 7A can be selected from an optionally substituted Ci-24 alkyl, an optionally substituted C3-24 alkenyl, an optionally substituted C3-24 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl(Ci-6 alkyl).
  • one of R 6A and R 7A can be hydrogen, and the other of R and R can be an optionally substituted Ci-24 alkyl.
  • R 7A can be independently selected from an optionally substituted Ci-24 alkyl, an optionally substituted C3-24 alkenyl, an optionally substituted C3-24 alkynyl, an optionally substituted C3- 6 cycloalkyl, an optionally substituted C3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl(Ci-6 alkyl).
  • both R 6A and R 7A can be an optionally substituted Ci-24 alkyl.
  • both R 6A and R 7A can be an optionally substituted C3-24 alkenyl.
  • R 6A and R 7A can be independently an optionally substituted version of the following: myristoleyl, myristyl, palmitoleyl, palmityl, sapienyl, oleyl, elaidyl, vaccenyl, linoleyl, a-linolenyl, arachidonyl, eicosapentaenyl, erucyl, docosahexaenyl, caprylyl, capryl, lauryl, stearyl, arachidyl, behenyl, lignoceryl and cerotyl.
  • At least one of R 6A and R 7A can be *-(CR 15A R 16A ) P - O-Ci-24 alkyl. In other embodiments, R 6A and R 7A can be both *-(CR 15A R 16A ) P -0-Ci-24 alkyl. In some embodiments, each R 15A and each R 16A can be hydrogen. In other embodiments, at least one of R 15A and R 16A can be an optionally substituted Ci-24 alkyl. In other embodiments, at least one of R 15A and R 16A can be an alkoxy (for example, benzoxy). In some embodiments, p can be 1. In other embodiments, p can be 2. In still other embodiments, p can be 3.
  • R 6A and R 7A can be *-(CR 17A R 18A ) q - O-C2-24 alkenyl. In other embodiments, R 6A and R 7A can be both *-(CR 17A R 18A ) q -0-C2-24 alkenyl. In some embodiments, each R 17A and each R 18A can be hydrogen. In other embodiments, at least one of R 17A and R 18A can be an optionally substituted Ci-24 alkyl. In some embodiments, q can be 1. In other embodiments, q can be 2. In still other embodiments, q can be 3.
  • the Ci-24 alkyl can be selected from caprylyl, capryl, lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, lignoceryl, and cerotyl
  • the C2-24 alkenyl can be selected from myristoleyl, palmitoleyl, sapienyl, oleyl, elaidyl, vaccenyl, linoleyl, a-linolenyl, arachidonyl, eicosapentaenyl, erucyl and docosahexaenyl.
  • R is at least one of R ⁇ 6A
  • R can be selected from
  • R 6A and R 7A can be selected from absent, hydrogen, an optionally substituted Ci-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl(Ci-6 alkyl).
  • At least one of R and R can be
  • R 19A and R 20A can be independently selected from hydrogen, an optionally substituted Ci-24 alkyl and an optionally substituted aryl; and R 21A can be selected from hydrogen, an optionally substituted Ci-24 alkyl, an optionally substituted aryl, an optionally substituted -O-Ci-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl, an optionally
  • R and R can be hydrogen.
  • at least one of R and R 20A can be an optionally substituted Ci-24 alkyl or an optionally substituted aryl.
  • R 21A can be an optionally substituted Ci-24 alkyl.
  • R 21A can be an optionally substituted aryl. In still other embodiments, R 21A can be an optionally substituted -O-Ci-24 alkyl or an optionally substituted -O-aryl. In some embodiments, R 21A can be an optionally substituted -O-Ci-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl or an optionally substituted -O-monocyclic heterocyclyl.
  • both R 6A and R 7A can be
  • R 22A and R 23A can be independently selected from hydrogen, an optionally substituted Ci-24 alkyl and an optionally substituted aryl;
  • R 24A can be independently selected from hydrogen, an optionally substituted Ci-24 alkyl, an optionally substituted aryl, an optionally substituted -O-Ci-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl, an optionally substituted -O-monocyclic
  • heterocyclyl and 2 ; and Z 4A can be independently O (oxygen) or S (sulfur).
  • R 22A and R 23A can be hydrogen.
  • at least one of R 22A and R 23A can be an optionally substituted Ci-24 alkyl or an optionally substituted aryl.
  • R 24A can be an optionally substituted Ci-24 alkyl.
  • R 24A can be an optionally substituted aryl.
  • R 24A can be an optionally substituted -O-Ci-24 alkyl or an optionally substituted -O-aryl.
  • Z 4A can be O (oxygen).
  • Z 4A can be or S (sulfur).
  • s can be 0.
  • s can be 1.
  • s can be 2.
  • s can be 3.
  • s can be 0, and R 24A can be
  • u can be 1.
  • u can be 2.
  • one or both of R and R can be isopropyloxycarbonyloxymethyl (POC).
  • R 6A and R 7A can be pivaloyloxymethyl (POM).
  • R 6A and R 7A can be both a isopropyloxycarbonyloxymethyl group, and form a bis(isopropyloxycarbonyloxymethyl) (bis(POC)) prodrug.
  • R 6A and R 7A can be both a pivaloyloxymethyl group, and form a bis(pivaloyloxymethyl) (bis(POM)) prodrug.
  • both R 6A and R 7A can be
  • R 26A and R" can be independently -C ⁇ N or an optionally substituted substituent selected from C2-8 organylcarbonyl, C2-8 alkoxycarbonyl and C2-8 organylaminocarbonyl;
  • R 28A can be selected from hydrogen, an optionally substituted Ci-24-alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and an optionally substituted C3-6 cycloalkenyl; and r can be 1 or 2.
  • R 6A and R 7A can be both an optionally substituted aryl. In some embodiments, at least one of R 6A and R 7A can be an optionally substituted aryl. For example, both R 6A and R 7A can be an optionally substituted phenyl or an optionally substituted naphthyl. When substituted, the substituted aryl can be substituted with 1, 2, 3 or more than 3 substituents. When more the two substituents are present, the substituents can be the same or different. In some embodiments, when at least one of R 6A and R 7A is a substituted phenyl, the substituted phenyl can be a para-, ortho- or meta-substituted phenyl.
  • R 6A and R 7A can be both an optionally substituted aryl(Ci-6 alkyl). In some embodiments, at least one of R 6A and R 7A can be an optionally substituted aryl(Ci-6 alkyl). For example, both R 6A and R 7A can be an optionally substituted benzyl. When substituted, the substituted benzyl group can be substituted with 1, 2, 3 or more than 3 substituents. When more the two substituents are present, the substituents can be the same or different. In some embodiments, the aryl group of the aryl(Ci-6 alkyl) can be a para-, ortho- or meta-substituted phenyl.
  • R 6A and R 7A can be both
  • R 25A can be hydrogen.
  • R 25A can be an optionally substituted Ci-24 alkyl.
  • R 25A can be an optionally substituted aryl.
  • R 25A can be a Ci-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained).
  • t can be 0.
  • t can be 1.
  • one or both of R 6A and R 7A can be a S-acylthioethyl (SATE).
  • R and R can be
  • At least one of R and R can b
  • R 29A can be hydrogen. In other embodiments, R 29A can be an optionally substituted Ci-24 alkyl. In some embodiments, R 29A can be a C1-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and t-butyl. In still other embodiments, R 29A can be an optionally substituted aryl, such as an optionally substituted phenyl or an optionally substituted naphthyl. In some embodiments, R 6A and R 7A can be both a dioxolenone group and form a dioxolenone prodrug. [0140] In some embodiments, R can be
  • R 7A can be absent or hydrogen
  • R 12A , R 13A and R 14A can be independently absent or hydrogen
  • m can be 0 or 1.
  • m can be 0, and R 7A , R 12A and R 13A can be independently absent or hydrogen.
  • m can be 1, and R 7A , R 12A , R 13A and R 14A can be independently absent or hydrogen.
  • R 6A can be diphosphate, when Z 1A is oxygen, or an alpha-thiodiphosphate, when Z 1A is sulfur.
  • R 6A can be triphosphate, when Z 1A is oxygen, or an alpha-thiotriphosphate, when Z 1A is sulfur.
  • R 6A and R 7A can be taken together to form an
  • R can be an optionally substituted
  • the ring When substituted, the ring can be substituted 1, 2, 3 or 3 or more times. When substituted with multiple sub substituents can be the same or different. In some
  • the ring when R 3A is , the ring can be substituted with an optionally substituted aryl group and/or an optionally substituted heteroaryl.
  • An example of a suitable heteroaryl is pyridinyl.
  • R 6A and R 7A can be taken together to form an
  • R 6A and R 7A can form a cyclic l -aryl-l,3-propanyl ester (HepDirect) prodrug moiety.
  • R 6A and R 7A can be taken together to form an
  • R can form a cyclosaligenyl (cycloSal) prodrug.
  • R 6A and R 6A are identical to each other.
  • R 6A and R 7A can be different.
  • Z can be oxygen. In other embodiments, Z can be sulfur.
  • R 8A can be selected from absent, hydrogen, an optionally substituted Ci-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3- 6 cycloalkyl and an optionally substituted C3-6 cycloalkenyl; and R 9A can be independently selected from an optionally substituted Ci-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and an optionally substituted C3-6 cycloalkenyl.
  • R is hydrogen,
  • R can be hydrogen, and R can be an optionally substituted Ci-6 alkyl.
  • suitable Ci-6 alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight- chained) and hexyl (branched and straight-chained).
  • R 8A can be hydrogen
  • R 9A can be NR 30A R 31A
  • R 30 and R 31 can be independently selected from hydrogen, an optionally substituted Ci-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and an optionally substituted C3-6 cycloalkenyl.
  • R 8A can be absent or hydrogen; and R 9A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.
  • R 8A can be an optionally substituted aryl; and R 9A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.
  • R 8A can be an optionally substituted heteroaryl; and R 9A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.
  • R 9A can be an amino acid selected from alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and ester derivatives thereof.
  • the amino acid can have various stereochemical configurations.
  • the amino acid can be racemic, an L-stereoisomer, a D-stereoisomer or a mixture of L- and D-stereoisomers that is enriched in one or the other of the stereoisomers.
  • the L-stereoisomer content of the amino acid is at least about 90%, at least about 95%, or at least about 99%, by weight based on the mixture of L- and D-stereoisomers.
  • an optionally substituted N-linked amino acid ester derivatives include optionally substituted versions of the following: alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester.
  • R can have the structure wherein R 33A can be selected from hydrogen, an optionally substituted Ci-6-alkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(Ci-6 alkyl) and an optionally substituted haloalkyl; R 34A can be selected from hydrogen, an optionally substituted Ci-6 alkyl, an optionally substituted Ci-6 haloalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted Ce aryl, an optionally substituted C10 aryl and an optionally substituted aryl(Ci-6 alkyl); and R 35A can be hydrogen or an optionally substituted Ci-4-alkyl; or R 34A and R 35A can be taken together to form an optionally substituted C3-6 cycloalkyl.
  • the amino acid portion of the optionally substituted N-linked amino acid ester derivatives can have the various stereochemical configurations that are
  • R is
  • R 33A is Ci-6 alkyl.
  • R 34A when R 34A is substituted, R 34A can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino.
  • substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino.
  • R 34A can be an unsubstituted Ci-6-alkyl, such as those described herein.
  • R 34A can be hydrogen.
  • R 34A can be methyl.
  • R 33A can be an optionally substituted Ci-6 alkyl.
  • optionally substituted Ci-6-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight- chained) and hexyl (branched and straight- chained).
  • R 33A can be methyl or isopropyl.
  • R 33A can be ethyl or neopentyl. In other embodiments, R 33A can be an optionally substituted C3-6 cycloalkyl. Examples of optionally substituted C3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In an embodiment, R 33A can be an optionally substituted cyclohexyl. In still other embodiments, R 33A can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R 33A can be an optionally substituted aryl(Ci-6 alkyl).
  • R 33A can be an optionally substituted benzyl. In some embodiments, R 33A can be an optionally substituted Ci-6 haloalkyl, for example, CF3. In some embodiments, R 35A can be hydrogen. In other embodiments, R 35A can be an optionally substituted Ci-4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R 35A can be methyl. In some embodiments, R 34A and R 35A can be taken together to form an optionally substituted C3-6 cycloalkyl.
  • optionally substituted C3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the carbon to which R 34A and R 35A are attached may be a chiral center.
  • the carbon to which R 34A and R 35A are attached may be a (R)- chiral center.
  • the carbon to which R 34A and R 35A are attached may be a (S)-chiral center.
  • R 5A when R 5A is Z 2A can be O
  • R 5A when R 5A is a compound of Formula (I) can be a phosphoramidate prodrug, such as an aryl phosphoramidate prodrug.
  • R can be R 11 A In some embodiments,
  • R 10A and R 11A can be both an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.
  • one or both of R 10A and R 11A can be an amino acid independently selected from alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and ester derivatives thereof.
  • the amino acid can have various stereochemical configurations.
  • the amino acid can be racemic, an L-stereoisomer, a D-stereoisomer or a mixture of L- and D-stereoisomers that is enriched in one or the other of the stereoisomers.
  • the L-stereoisomer content of the amino acid is at least about 90%, at least about 95%, or at least about 99%, by weight based on the mixture of L- and D-stereoisomers.
  • R 10A and R 11A can be an optionally substituted version of the following: alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester.
  • R 10A and R 11A can be an optionally substituted version of the following: alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester.
  • R 10A and R 11A can be an optionally substituted version of the following: alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester.
  • R 10A and R 11A can
  • R 36A can be selected from hydrogen, an optionally substituted Ci-6-alkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(Ci-6 alkyl) and an optionally substituted haloalkyl;
  • R 37A can be selected from hydrogen, an optionally substituted Ci-6 alkyl, an optionally substituted Ci-6 haloalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted Ce aryl, an optionally substituted C10 aryl and an optionally substituted aryl(Ci-6 alkyl);
  • R 38A can be hydrogen or an optionally substituted Ci-4-alkyl; or R 37A and
  • R 38A can be taken together to form an optionally substituted C3-6 cycloalkyl.
  • R 37A When R 37A is substituted, R 37A can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In some embodiments,
  • R 37A can be an unsubstituted Ci-6-alkyl, such as those described herein.
  • R can be hydrogen.
  • R can be methyl.
  • R 36A can be an optionally substituted Ci-6 alkyl.
  • optionally substituted Ci-6-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight- chained) and hexyl (branched and straight- chained).
  • R 36A can be methyl or isopropyl.
  • R 36A can be ethyl or neopentyl.
  • other embodiments
  • R 36A can be an optionally substituted C3-6 cycloalkyl.
  • optionally substituted C3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R 36A can be an optionally substituted cyclohexyl.
  • R 36A can be an optionally substituted aryl, such as phenyl and naphthyl.
  • R 36A can be an optionally substituted aryl(Ci-6 alkyl).
  • R 36A can be an optionally substituted benzyl.
  • R 36A can be an optionally substituted Ci-6 haloalkyl, for example, CF3.
  • R 38A can be hydrogen.
  • R 38A can be an optionally substituted Ci-4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
  • R 38A can be methyl.
  • R 37A and R 38A can be taken together to form an optionally substituted C3-6 cycloalkyl.
  • optionally substituted C3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the carbon to which R 37A and R 38A are attached may be a chiral center.
  • the carbon to which R 37A and R 38A are attached may be a (R)- chiral center.
  • the carbon to which R 37A and R 38A are attached may be a (S)-chiral center.
  • Z can be O (oxygen). In other embodiments, Z
  • (I) can be a phosphonic diamide prodrug.
  • the groups attached to the phosphorus can be easily removed by esterases, proteases and/or other enzymes. In some embodiments, the groups attached to the phosphorus can be removed by simple hydrolysis. Inside the cell, the phosphate thus released may then be metabolized by cellular enzymes to the diphosphate or the active triphosphate. Furthermore, in some embodiments, varying the substituents on a compound described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt of any of the foregoing, can help maintain the efficacy of the compound by reducing undesirable effects.
  • R 39A can be a substituted Ci-12 alkyl. In other embodiments, R 39A can be an unsubstituted Ci-12 alkyl. [0158] In still other embodiments, R can be an optionally substituted O-linked amino acid. Examples of suitable O-linked amino acids include alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.
  • suitable O-linked amino acids include alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threon
  • suitable amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine.
  • O-linked amino acid can be selected such that -OR 5A has the structure wherein R can be selected from hydrogen, an optionally substituted Ci-
  • R 41A can be hydrogen or an optionally substituted Ci-4-alkyl; or R 40A and
  • R 41A can be taken together to form an optionally substituted C3-6 cycloalkyl.
  • R 40A When R 40A is substituted, R 40A can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino.
  • R 40A can be an unsubstituted Ci-6-alkyl, such as those described herein.
  • R 40A can be hydrogen.
  • R 40A can be methyl.
  • R 41A can be hydrogen.
  • R 41A can be an optionally substituted Ci-4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert- butyl. In an embodiment, R 41A can be methyl.
  • the carbon to which R 40A and R 41A are attached may be a chiral center. In some embodiment, the carbon to which R 40A and R 41A are attached may be a (R)-chiral center. In other embodiments, the carbon to which R 40A and R 41A are attached may be a (S)- chiral center. include the following:
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof is a panviral compound.
  • panviral refers to a compound (e.g., a nucleoside analog or a nucleotide analog) that exhibits pharmaceutically significant activity against viruses in two or more families of viruses. The degree to which a compound exhibits pharmaceutically significant activity can be determined by using a validated assay that is appropriate for the virus being tested. Such assay methods are known to those skilled in the art and include the assay methods described in the Examples below.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof is considered to be panviral if it exhibits an ECso and/or ICso value of 100 ⁇ or less in at least one assay for a virus in a first virus family and also exhibits an ECso and/or IC50 value of 100 ⁇ or less in at least one assay for a virus in a second virus family that is different from the first family. It will be apparent to those skilled in the art that compounds having greater activity are also considered panviral.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof is also considered to be panviral if it exhibits an EC50 and/or IC50 value of 10 ⁇ or less in at least one assay for a virus in a first virus family and also exhibits an EC50 and/or IC50 value of 100 ⁇ or less in at least one assay for a virus in a second virus family that is different from the first family.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof is a low toxicity compound.
  • the term "low toxicity” refers to a compound (e.g., a nucleoside analog or a nucleotide analog) that exhibits pharmaceutically insignificant toxicity when tested using a validated toxicity assay that is appropriate for the virus being tested. Such assay methods are known to those skilled in the art and include the assay methods described in the Examples below.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof is considered to exhibit pharmaceutically insignificant toxicity if it exhibits a 50% cytotoxic concentration (CC50) value of 10 ⁇ or more. It will be apparent to those skilled in the art that less toxic compounds are also considered low toxicity.
  • a compound is also considered to exhibit pharmaceutically insignificant toxicity if it exhibits a CC50 value of 100 ⁇ or more.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof is a low toxicity panviral nucleoside analog.
  • low toxicity panviral refers to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that is both low toxicity and panviral, as described above.
  • a pharmaceutical composition that can include an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • the pharmaceutical composition can include a single diastereomer of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (for example, a single diastereomer present in the pharmaceutical composition at a concentration of greater than 99% compared to the total concentration of the other diastereomers).
  • the pharmaceutical composition can include a mixture of diastereomers of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition can include a concentration of one diastereomer of > 50%, > 60%, > 70%, > 80%, > 90%, > 95%, or > 98%, as compared to the total concentration of the other diastereomers.
  • the pharmaceutical composition includes a 1 : 1 mixture of two diastereomers of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • composition refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • a pharmaceutical composition is suitable for human and/or veterinary applications.
  • physiologically acceptable defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.
  • a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • a "diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
  • an "excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • a "diluent” is a type of excipient.
  • the pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counter ions.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • a panviral treatment as described elsewhere herein is formulated for administration to a subject having a viral infection.
  • a panviral treatment that has been formulated in a particular manner, e.g., in the form of a pharmaceutical composition that facilitates administration by a particular route (e.g., oral, aerosol, injection, etc.) and/or with appropriate labeling for treatment of the condition for which it is indicated.
  • An embodiment provides a panviral treatment formulated for administration to a subject having a Picornaviridae, Flaviviridae, Filoviridae, Pneumoviridae and/or Coronaviridae viral infection.
  • Some embodiments disclosed herein relate to a method of treating and/or ameliorating a Picornaviridae viral infection that can include administering to a subject infected with the Picornaviridae virus an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • compounds described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions disclosed herein relate to a method of treating and/or ameliorating a Picornaviridae viral infection that can include administering to a subject identified as suffering from the viral infection an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a subject identified as suffering from the viral infection an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • Some embodiments described herein relate to methods of using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and/or treating a Picornaviridae viral infection that can include administering to a subject infected with the Picornaviridae virus an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • Still other embodiments described herein relate to one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof) that can be used for ameliorating and/or treating a Picornaviridae viral infection by administering to a subject infected with the Picornaviridae virus an effective amount of one or more compounds described herein.
  • compounds described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Some embodiments disclosed herein relate to methods of ameliorating and/or treating a Picornaviridae viral infection that can include contacting a cell infected with the Picornaviridae virus with an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • compounds described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and/or treating a Picornaviridae viral infection that can include contacting a cell infected with the Picornaviridae virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), that can be used for ameliorating and/or treating a Picornaviridae viral infection by contacting a cell infected with the Picornaviridae virus with an effective amount of said compound(s).
  • Some embodiments disclosed herein relate to methods of inhibiting replication of a Picornaviridae virus that can include contacting a cell infected with the Picornaviridae virus with an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for inhibiting replication of a Picornaviridae virus that can include contacting a cell infected with the Picornaviridae virus with an effective amount of said compound(s). Still other embodiments described herein relate to a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), that can be used for inhibiting replication of a Picornaviridae virus by contacting a cell infected with the Picornaviridae virus with an effective amount of said compound(s).
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can inhibit a RNA dependent RNA polymerase of a Picornaviridae virus, and thus, inhibit the replication of RNA.
  • a polymerase of a Picornaviridae virus can be inhibited by contacting a cell infected with the Picornaviridae virus with a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • the Picornaviridae virus can be selected from an Aphthovirus, an Enterovirus, a Rhinovirus, a Hepatovirus and a Parechovirus.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a compound described herein can inhibit replication of a Rhinovirus.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be effective against a Rhinovirus, and thereby ameliorate one or more symptoms of a Rhinovirus infection.
  • Suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in time to seroconversion (virus undetectable in patient serum), a reduction of morbidity or mortality in clinical outcomes, and/or other indicator(s) of disease response.
  • Further indicators include one or more overall quality of life health indicators, such as reduced illness duration, reduced illness severity, reduced time to return to normal health and normal activity, and reduced time to alleviation of one or more symptoms.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can result in the reduction, alleviation or positive indication of one or more of the aforementioned indicators compared to an untreated subject.
  • Effects/symptoms of a Picornaviridae viral infection are described herein, and include, but are not limited to, fever, blisters, rash, meningitis, conjunctivitis, acute hemorrhagic conjunctivitis (AHC), sore throat, nasal congestion, runny nose, sneezing, coughing, loss of appetite, muscle aches, headache, fatigue, nausea, jaundice, encephalitis, herpangina, myocarditis, pericarditis, meningitis, Bornholm disease, myalgia, nasal congestion, muscle weakness, loss of appetite, fever, vomiting, abdominal pain, abdominal discomfort, dark urine and muscle pain.
  • Some embodiments disclosed herein relate to a method of treating and/or ameliorating a Flaviviridae viral infection that can include administering to a subject infected with the Flaviviridae virus an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a method of treating and/or ameliorating a Flaviviridae viral infection can include administering to a subject infected with the Flaviviridae virus an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions disclosed herein relate to a method of treating and/or ameliorating a Flaviviridae viral infection that can include administering to a subject an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a method of treating and/or ameliorating a Flaviviridae viral infection can include administering to a subject an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • Some embodiments described herein relate to methods of using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and/or treating a Flaviviridae viral infection that can include administering an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Still other embodiments described herein relate to one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof) that can be used for ameliorating and/or treating a Flaviviridae viral infection by administering to a subject an effective amount of one or more compounds described herein.
  • Some embodiments disclosed herein relate to methods of ameliorating and/or treating a Flaviviridae viral infection that can include contacting a cell infected with the Flaviviridae virus with an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • compounds described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and/or treating a Flaviviridae viral infection that can include contacting a cell infected with the Flaviviridae virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), that can be used for ameliorating and/or treating a Flaviviridae viral infection by contacting a cell infected with the Flaviviridae virus with an effective amount of said compound(s).
  • Some embodiments disclosed herein relate to methods of inhibiting replication of a Flaviviridae virus that can include contacting a cell infected with the Flaviviridae virus with an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for inhibiting replication of a Flaviviridae virus that can include contacting a cell infected with the Flaviviridae virus with an effective amount of said compound(s). Still other embodiments described herein relate to a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), that can be used for inhibiting replication of a Flaviviridae virus by contacting a cell infected with the Flaviviridae virus with an effective amount of said compound(s).
  • a polymerase of a Flaviviridae virus can be inhibited by contacting a cell infected with the Flaviviridae virus with a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), and thereby, inhibit the replication of RNA.
  • a compound described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Some embodiments disclosed herein relate to methods of ameliorating and/or treating a HCV infection that can include contacting a cell infected with HCV with an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • Other embodiments described herein relate to methods of using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and/or treating a HCV infection that can include contacting a cell infected with HCV with an effective amount of said compound(s).
  • Still other embodiments described herein relate to one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), that can be used for ameliorating and/or treating a HCV infection by contacting a cell infected with HCV with an effective amount of said compound(s).
  • compounds described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Some embodiments described herein relate to a method of inhibiting NS5B polymerase activity that can include contacting a cell infected with hepatitis C virus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • NS5B is believed to be an RNA-dependent RNA polymerase involved in the replication of HCV RNA.
  • Some embodiments described herein relate to a method of inhibiting NS5B polymerase activity that can include administering to a subject infected with hepatitis C virus an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can inhibit a RNA dependent RNA polymerase, and thus, inhibit the replication of HCV RNA.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can inhibit a HCV polymerase (for example, NS5B polymerase).
  • Some embodiments described herein relate to a method of treating a condition selected from liver fibrosis, liver cirrhosis and liver cancer in a subject suffering from one or more of the aforementioned liver conditions that can include administering to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the liver condition is caused by a HCV infection.
  • Some embodiments described herein relate to a method of increasing liver function in a subject having a HCV infection that can include administering to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • this method can include slowing or halting the progression of liver disease.
  • the course of the disease can be reversed, and stasis or improvement in liver function is contemplated.
  • liver fibrosis, liver cirrhosis and/or liver cancer can be treated; liver function can be increased; virus-caused liver damage can be reduced or eliminated; progression of liver disease can be slowed or halted; the course of the liver disease can be reversed and/or liver function can be improved or maintained by contacting a cell infected with hepatitis C virus with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof.)
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • genotypes of HCV there are a variety of genotypes of HCV, and a variety of subtypes within each genotype. For example, at present it is known that there are eleven (numbered 1 through 11) main genotypes of HCV, although others have classified the genotypes as 6 main genotypes. Each of these genotypes is further subdivided into subtypes (la-lc; 2a-2c; 3a-3b; 4a-4e; 5a; 6a; 7a- 7b; 8a-8b; 9a; 10a; and 11a).
  • an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition that includes an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt of any of the foregoing can be effective to treat at least one genotype of HCV.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a compound of Formula (I), or a pharmaceutical acceptable salt thereof can be more effective against a larger number of HCV genotypes than the standard of care. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be more effective against a particular HCV genotype than the standard of care (such as genotype 1, 2, 3, 4, 5 and/or 6).
  • Suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy, a reduction of morbidity or mortality in clinical outcomes, a reduction in the rate of liver function decrease; stasis in liver function; improvement in liver function; reduction in one or more markers of liver dysfunction, including alanine transaminase, aspartate transaminase, total bilirubin, conjugated bilirubin, gamma glutamyl transpeptidase and/or other indicator of disease response.
  • successful therapy with an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can reduce the incidence of liver cancer in HCV infected subjects.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof
  • the Flavivirus can be a West Nile virus.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof
  • a dengue virus infection can cause dengue hemorrhagic fever and/or dengue shock syndrome.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof
  • the Flavivirus can be yellow fever virus.
  • the Flavivirus can be an encephalitis virus from within the Flavivirus genus.
  • encephalitis viruses include, but are not limited to, Japanese encephalitis virus, St. Louis encephalitis virus and tick borne encephalitis.
  • the Flavivirus can be a Zika virus.
  • Some embodiments disclosed herein relate to a method of treating and/or ameliorating a Filoviridae viral infection that can include administering to a subject infected with the Filoviridae virus an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • compounds described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions disclosed herein relate to a method of treating and/or ameliorating a Filoviridae viral infection that can include administering to a subject identified as suffering from the viral infection an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a subject identified as suffering from the viral infection an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • Some embodiments described herein relate to methods of using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and/or treating a Filoviridae viral infection that can include administering to a subject infected with the Filoviridae virus an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • Still other embodiments described herein relate to one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof) that can be used for ameliorating and/or treating a Filoviridae viral infection by administering to a subject infected with the Filoviridae virus an effective amount of one or more compounds described herein.
  • compounds described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Some embodiments disclosed herein relate to methods of ameliorating and/or treating a Filoviridae viral infection that can include contacting a cell infected with the Filoviridae virus with an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and/or treating a Filoviridae viral infection that can include contacting a cell infected with the Filoviridae virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), that can be used for ameliorating and/or treating a Filoviridae viral infection by contacting a cell infected with the Filoviridae virus with an effective amount of said compound(s).
  • Some embodiments disclosed herein relate to methods of inhibiting replication of a Filoviridae virus that can include contacting a cell infected with the Filoviridae virus with an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for inhibiting replication of a Filoviridae virus that can include contacting a cell infected with the Filoviridae virus with an effective amount of said compound(s). Still other embodiments described herein relate to a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), that can be used for inhibiting replication of a Filoviridae virus by contacting a cell infected with the Filoviridae virus with an effective amount of said compound(s).
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can inhibit a RNA dependent RNA polymerase of a Filoviridae virus, and thus, inhibit the replication of RNA.
  • a polymerase of a Filoviridae virus can be inhibited by contacting a cell infected with the Filoviridae virus with a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof
  • a compound described herein can be used to ameliorate and/or treat a Filoviridae viral infection.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof
  • the Filoviridae virus can be selected from an Ebolavirus, a Marburgvirus and a Cuevavirus.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be effective against an Ebolavirus, and thereby ameliorate one or more symptoms of an Ebolavirus infection.
  • Ebolavirus Ebola virus
  • REBOV Reston ebolavirus
  • SEBOV Sudan ebolavirus
  • TAFV Tai Forest ebolavirus
  • BEBOV Bundibugyo ebolavirus
  • Marburgvirus Marburg virus
  • MARV Marburg virus
  • RAW Ravn virus
  • Some embodiments disclosed herein relate to a method of treating and/or ameliorating a Pneumoviridae viral infection that can include administering to a subject infected with the Pneumoviridae virus an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • compounds described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions disclosed herein relate to a method of treating and/or ameliorating a Pneumoviridae viral infection that can include administering to a subject identified as suffering from the viral infection an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a subject identified as suffering from the viral infection an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • Some embodiments described herein relate to methods of using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and/or treating a Pneumoviridae viral infection that can include administering to a subject infected with the Pneumoviridae virus an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • Still other embodiments described herein relate to one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof) that can be used for ameliorating and/or treating a Pneumoviridae viral infection by administering to a subject infected with the Pneumoviridae virus an effective amount of one or more compounds described herein.
  • compounds described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Some embodiments disclosed herein relate to methods of ameliorating and/or treating a Pneumoviridae viral infection that can include contacting a cell infected with the Pneumoviridae virus with an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • compounds described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and/or treating a Pneumoviridae viral infection that can include contacting a cell infected with the Pneumoviridae virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), that can be used for ameliorating and/or treating a Pneumoviridae viral infection by contacting a cell infected with the Pneumoviridae virus with an effective amount of said compound(s).
  • Some embodiments disclosed herein relate to methods of inhibiting replication of a Pneumoviridae virus that can include contacting a cell infected with the Pneumoviridae virus with an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for inhibiting replication of a Pneumoviridae virus that can include contacting a cell infected with the Pneumoviridae virus with an effective amount of said compound(s). Still other embodiments described herein relate to a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), that can be used for inhibiting replication of a Pneumoviridae virus by contacting a cell infected with the Pneumoviridae virus with an effective amount of said compound(s).
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can inhibit a RNA dependent RNA polymerase of a Pneumoviridae virus, and thus, inhibit the replication of RNA.
  • a polymerase of a Pneumoviridae virus can be inhibited by contacting a cell infected with the Pneumoviridae virus with a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a compound described herein can be used to ameliorate and/or treat a Pneumoviridae viral infection.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof
  • the Pneumovirus virus can be a Human respiratory syncytial virus (HRSV), such as HRSV-A2, HRSV-B1 and HRSV-S2. HRSV can cause respiratory tract infections, bronchiolitis, pneumonia and severe lower respiratory tract disease.
  • HRSV Human respiratory syncytial virus
  • Some embodiments disclosed herein relate to a method of treating and/or ameliorating a Coronaviridae viral infection that can include administering to a subject infected with the Coronaviridae virus an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • compounds described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a subject identified as suffering from the viral infection an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • Some embodiments described herein relate to methods of using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and/or treating a Coronaviridae viral infection that can include administering to a subject infected with the Coronaviridae virus an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • Still other embodiments described herein relate to one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof) that can be used for ameliorating and/or treating a Coronaviridae viral infection by administering to a subject infected with the Coronaviridae virus an effective amount of one or more compounds described herein.
  • compounds described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Some embodiments disclosed herein relate to methods of ameliorating and/or treating a Coronaviridae viral infection that can include contacting a cell infected with the Coronaviridae virus with an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and/or treating a Coronaviridae viral infection that can include contacting a cell infected with the Coronaviridae virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), that can be used for ameliorating and/or treating a Coronaviridae viral infection by contacting a cell infected with the Coronaviridae virus with an effective amount of said compound(s).
  • Some embodiments disclosed herein relate to methods of inhibiting replication of a Coronaviridae virus that can include contacting a cell infected with the Coronaviridae virus with an effective amount of one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to using one or more compounds described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for inhibiting replication of a Coronaviridae virus that can include contacting a cell infected with the Coronaviridae virus with an effective amount of said compound(s). Still other embodiments described herein relate to a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), that can be used for inhibiting replication of a Coronaviridae virus by contacting a cell infected with the Coronaviridae virus with an effective amount of said compound(s).
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can inhibit a RNA dependent RNA polymerase of a Coronaviridae virus, and thus, inhibit the replication of RNA.
  • a polymerase of a Coronaviridae virus can be inhibited by contacting a cell infected with the Coronaviridae virus with a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a compound described herein can be used ameliorate and/or treat a Coronaviridae viral infection.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof
  • the Coronavirus virus can be a human alpha coronavirus (HRSV) or a human beta coronavirus.
  • coronaviruses that can infect people are: alpha coronaviruses 229E and NL63, and beta coronaviruses OC43, HKU1, SARS-CoV (the coronavirus that causes severe acute respiratory syndrome, or SARS), and MERS-CoV (the coronavirus that causes Middle East Respiratory Syndrome, or MERS).
  • Suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in time to seroconversion (virus undetectable in patient serum), a reduction of morbidity or mortality in clinical outcomes, and/or other indicator(s) of disease response.
  • Further indicators include one or more overall quality of life health indicators, such as reduced illness duration, reduced illness severity, reduced time to return to normal health and normal activity, and reduced time to alleviation of one or more symptoms.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can result in the reduction, alleviation or positive indication of one or more of the aforementioned indicators compared to a subject who is receiving the standard of care or an untreated subject.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can result in a reduction in the length and/or severity of one or more symptoms associated with a Picornaviridae, Flaviviridae, Filoviridae, Pne moviridae and/or Coronaviridae viral infection compared to a subject who is receiving the standard of care or an untreated subject.
  • Table 1 provides some embodiments of the percentage improvements obtained using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as compared to the standard of care or an untreated subject.
  • Examples include the following: in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a percentage of non-responders that is 10% less than the percentage of non- responders receiving the standard of care; in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a duration of illness that is in the range of about 10% to about 30% less than compared to the duration of illness experienced by a subject who is untreated for the infection; and in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a severity of a symptom (such as one of those described herein) that is 25% less than compared to the severity of the same symptom experienced by a subject who is untreated for the infection. Methods of quantifying the severity of a side effect and/or symptom are known to those skilled in the art. Table 1
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof is a panviral nucleoside analog.
  • Various embodiments provide a panviral treatment that comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the term "panviral treatment” refers to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that is panviral as described above. Such panviral treatments are thus effective to treat two or more viral infections, where the viruses that cause the infections are caused by viruses from two or more virus families.
  • the panviral treatment comprises a compound, or a pharmaceutically acceptable salt thereof, that is effective to treat viral infections caused by viruses in two or more families selected from the group consisting of Picornaviridae, Flaviviridae, Filoviridae, Pneumoviridae and Coronaviridae.
  • families selected from the group consisting of Picornaviridae, Flaviviridae, Filoviridae, Pneumoviridae and Coronaviridae.
  • the panviral treatment comprises a compound, or a pharmaceutically acceptable salt thereof, that is effective to treat viral infections selected from a Rhinovirus infection in the Picornaviridae family; a Dengue virus infection or a Hepacivirus infection in the Flaviviridae family; an Ebolavirus infection in the Filoviridae family; a human respiratory syncytial virus (HRSV) infection in the Pneumoviridae family; and a human a-coronavirus viral infection and/or a human ⁇ - coronavirus viral infection in the Coronaviridae family.
  • the panviral treatment comprises a compound, or a pharmaceutically acceptable salt thereof, having low toxicity as described elsewhere herein. Examples of panviral treatments include those comprising compounds 1-15 as described in the Examples below, and pharmaceutically acceptable salts thereof.
  • the compound can be a compound of Formula (I), wherein the compound of Formula (I) is a mono, di, or triphosphate, or a pharmaceutically acceptable salt of any of the foregoing.
  • the compound can be a compound of Formula (I), wherein the compound of Formula (I) is a thiomonophosphate, alpha-thiodiphosphate, or alpha-thiotriphosphate, or a pharmaceutically acceptable salt of any of the foregoing.
  • the compound of Formula (I), or a pharmaceutical acceptable salt of any of the foregoing, that can be used to ameliorate and/or treat a Picornaviridae, Flaviviridae, Filoviridae, Pneumoviridae and/or Coronaviridae viral infection and/or inhibit replication of a Picornaviridae, Flaviviridae, Filoviridae, Pneumoviridae and/or Coronaviridae virus can be any of the embodiments described herein.
  • a "subject” refers to an animal that is the object of treatment, observation or experiment.
  • Animal includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject is human.
  • treating do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the patient's overall feeling of well-being or appearance.
  • an effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.
  • the effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
  • the determination of effective dosage levels that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials and in vitro studies.
  • the dosage may range broadly, depending upon the desired effects and the therapeutic indication. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of each active ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the subject.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered less frequently compared to the frequency of administration of an agent within the standard of care.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered one time per day.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered one time per day to a subject suffering from a picornavirus infection.
  • the total time of the treatment regime with a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be less compared to the total time of the treatment regime with the standard of care.
  • human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage.
  • a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • dosages may be calculated as the free base.
  • the compounds disclosed herein in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
  • the compounds disclosed herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof, can be used in combination with one or more additional agent(s) for treating, ameliorating and/or inhibiting a Picornaviridae, Flaviviridae, Filoviridae, Pneumoviridae and/or Coronaviridae viral infection.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered with one or more additional agent(s) together in a single pharmaceutical composition.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered in one pharmaceutical composition, and at least one of the additional agents can be administered in a second pharmaceutical composition.
  • one or more of the additional agents can be in a first pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.
  • the dosing amount(s) and dosing schedule(s) when using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents are within the knowledge of those skilled in the art.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered in addition to that therapy, or in place of one of the agents of a combination therapy, using effective amounts and dosing protocols as described herein.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered prior to all additional agents.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered prior to at least one additional agent.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered concomitantly with one or more additional agent(s).
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered subsequent to the administration of at least one additional agent.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered subsequent to the administration of all additional agents.
  • the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) can result in an additive effect.
  • the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, used in combination with one or more additional agent(s) can result in a synergistic effect.
  • the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, used in combination with one or more additional agent(s) can result in a strongly synergistic effect.
  • the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) is not antagonistic.
  • the term “antagonistic” means that the activity of the combination of compounds is less compared to the sum of the activities of the compounds in combination when the activity of each compound is determined individually (i.e. as a single compound).
  • the term “synergistic effect” means that the activity of the combination of compounds is greater than the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually.
  • the term “additive effect” means that the activity of the combination of compounds is about equal to the sum of the individual activities of the compound in the combination when the activity of each compound is determined individually.
  • a potential advantage of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) may be a reduction in the required amount(s) of one or more additional agent(s) that is effective in treating an a viral infection, as compared to the amount required to achieve same therapeutic result when one or more additional agent(s) are administered without a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Another potential advantage of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) is that the use of two or more compounds having different mechanism of actions can create a higher barrier to the development of resistant viral strains compared to the barrier when a compound is administered as monotherapy.
  • Additional advantages of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) may include little to no cross resistance between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) thereof; different routes for elimination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s); little to no overlapping toxicities between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s); little to no significant effects on cytochrome P450; little to no pharmacokinetic interactions between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s); greater percentage of subjects achieving a sustained viral response compared to when a compound is administered as monotherapy and/or a decrease in treatment time to achieve a sustained viral response compared to when a compound is administered as monotherapy.
  • examples of additional agents that can be used in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof include, but are not limited to, ribavirin and an interferon (including those described herein).
  • the compounds of Formula (I) illustrated in Tables 1 -3 can be prepared in various ways, using techniques known to those skilled in the art as guided by the detailed teachings provided herein.
  • the compounds of Formula (I) illustrated in Tables 1-3 can be readily prepared in view of the detailed teachings set forth herein including Examples 1-15 below as well as the reaction schemes illustrated in Figures 1-8.
  • Those skilled in the art will understand that a number of structures shown in Table 1-3 are stereospecific (or non-stereospecific) and/or are depicted as having unfilled valencies, and that isotopic and/or stereochemical variants, including racemates, diastereomers, enantiomers and/or deuterated versions, can be prepared in accordance with the guidance provided herein.
  • Neopentyl ((((2S,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-5-cyano-2- fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate
  • DIPEA DIEA
  • DIEA DIEA
  • fluorination of a compound of formula (V), where PG is benzyl is achieved using a fluorinating agent such as diethylaminosulfur trifluoride (DAST), and the like, in a suitable solvent such as toluene, DCM, and the like, at temperatures ranging from 0 °C to 60 °C.
  • a fluorinating agent such as diethylaminosulfur trifluoride (DAST), and the like
  • DAST diethylaminosulfur trifluoride
  • a compound of formula (VII) is prepared in two steps from a compound of formula (VI) where PG is benzyl.
  • a compound of formula (VII), where PG is benzyl and R 4A is H is prepared from D-ribofuranose in two steps.
  • D- ribofuranose is methylated employing an acid such as H2SO4, in MeOH.
  • protection with a suitable protecting group such as benzyl employing conditions known to one skilled in the art, provides a compound of formula (VII).
  • Removal of the methyl group in a compound of formula (VII), where R 4A is H is accomplished using an acid such a TFA, and the like, in water, for a period of 10-15 h, to provide a compound of formula (VQI), where PG is benzyl.
  • R 4A is CH2F
  • the process of Scheme 2 can be modified as indicated in Scheme 2 A.
  • a compound of formula (X) is prepared in two steps from a commercially available or synthetically accessible compound of formula (III), where HAL is Br, and a commercially available or synthetically accessible compound of formula (IX), where PG is benzyl, and R 4A is H or CH2F.
  • a compound of formula (III) such as 7-bromopyrrolo[2,l-f][l,2,4]triazin-4-amine is reacted with a base such as NaH and the like, in a suitable solvent such as THF, and the like, and 1 ,2- bis(chlorodimethylsilyl)ethane to provide a compound of formula (IV) which was not isolated but used directly in the next step.
  • a compound of formula (IV) is reacted with a base such as n-BuLi, t-BuLi, and the like, in a suitable solvent such as THF, Et 2 0, and the like, at a temperature of -78 °C, followed by the addition of a commercially available or synthetically accessible ribolactone compound of formula (IX) such as (3R,4S,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-5-(fluoromethyl)dihydrofuran-2(3H)- one, (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one, and the like, to provide a compound of formula (X).
  • a base such as n-BuLi, t-BuLi, and the like
  • a suitable solvent such as THF, Et 2 0, and the like
  • a cyano compound of formula (XI), where R is H and PG is benzyl is prepared from a compound of formula (X).
  • a compound of formula (X) is reacted with TMSCN and TMSOTf in a solvent such as DCM, and the like, at a temperature of about -78 °C, to provide a compound of formula (XT).
  • a reagent such as boron trichloride to provide a compound of formula (XII), where R 1A is CN and R 4A is H.
  • An azide compound of formula (XIII), where R 4A is N3, is prepared by the addition of iodine azide to the 4' -double bond of a compound of formula (XIV) in a regio and stereospecific manner.
  • iodine azide generated in situ from iodine monochloride and sodium azide
  • a compound of formula (XIV) where R 1A is CN
  • a solvent suitable such as DMF to provide an azide compound of formula (XIII), where R 4A is N3 and R 1A is CN.
  • a compound of formula (XIII), where R 1A is CN and R 4A is F, is protected to provide an methoxymethylene compound of formula (XVII).
  • Reaction of a compound of formula (XVII) in a nucleophilic substitution reaction with a nucleophile such as potassium benzoate, and the like, 18-crown-6, in a suitable solvent such as DMSO, DMF, and the like, at a temperature of about 100 °C provides a compound of formula (XVIII), where PG is benzoyl.
  • Deprotection of the benzoyl protecting group (PG) with ammonia in methanol provides a compound of formula (XIX), where R 1A is CN and R 4A is F.
  • DMDO dimethyldioxirane
  • Oxone potassium peroxymonosulfate
  • a compound of formula (XXII), where R 1A and R 4A are CN, and PG 2 is trimethylsilyl, is prepared by ring opening of the epoxide of a compound of formula (XXI) in the presence of a Lewis Acid such as InBn, TiCU, and the like, and cyanotrimethylsilane (TMSCN), in a suitable solvent such as DCM, and the like.
  • a Lewis Acid such as InBn, TiCU, and the like
  • TMSCN cyanotrimethylsilane
  • a chlorophosphoramidate of formula (XXV), where Z 3A is O, and R 9A is an N-linked amino acid or an optionally substituted N-linked amino acid ester derivative is prepared by reacting phenyl phosphorodichloridate with a commercially available or synthetically accessible amino acid or an optionally substituted amino acid ester derivative, a base such as triethylamine (TEA), and the like, in a suitable solvent such as DCM.
  • a suitable solvent such as DCM.
  • a chlorophosphoramidate compound of formula (XXV) is reacted with a compound of formula (XIX), where R is CN and R is F, in the presence of N-methylimidazole, in a suitable solvent such as ACN.
  • a suitable solvent such as ACN.
  • deprotection of the tethered oxomethylene is accomplished employing an acid such as HC1, HCOOH, and the like, in a suitable solvent such as dioxane, water, or a mixture thereof, to provide a compound of Formula (la), where R 1A is CN, R 2A and R 3A are H, and R 4A is F.
  • Compounds of Formula (I) may be converted to their corresponding salts using methods known to one of ordinary skill in the art.
  • an amine of Formula (I) is treated with trifluoroacetic acid, HC1, or citric acid in a solvent such as Et 2 0, CH2CI2, THF, MeOH, chloroform, or isopropanol to provide the corresponding salt form.
  • trifluoroacetic acid or formic acid salts are obtained as a result of reverse phase HPLC purification conditions.
  • Crystalline forms of pharmaceutically acceptable salts of compounds of Formula (I) may be obtained in crystalline form by recrystallization from polar solvents (including mixtures of polar solvents and aqueous mixtures of polar solvents) or from non- polar solvents (including mixtures of non-polar solvents).
  • Compounds prepared according to the schemes described above may be obtained as single forms, such as single enantiomers, by form-specific synthesis, or by resolution. Compounds prepared according to the schemes above may alternately be obtained as mixtures of various forms, such as racemic (1 : 1) or non-racemic (not 1 : 1) mixtures. Where racemic and non-racemic mixtures of enantiomers are obtained, single enantiomers may be isolated using conventional separation methods known to one of ordinary skill in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation. Where regioisomeric or diastereomeric mixtures are obtained, as applicable, single isomers may be separated using conventional methods such as chromatography or crystallization.
  • reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Where solutions were “dried,” they were generally dried over a drying agent such as Na 2 S0 4 or MgS0 4 . Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure. Reactions under microwave irradiation conditions were carried out in a Biotage Initiator or CEM (Microwave Reactor) Discover instrument.
  • RP HPLC reverse-phase high performance liquid chromatography
  • MS Mass spectra
  • Step A 7-Bromopyrrolo[2,l-f1[l,2,41triazin-4-amine.
  • pyrrolo[2,l- f][l,2,4]triazin-4-amine 2.1 g, 15.66 mmol, 1.00 equiv
  • DMF 20 mL
  • 1,3- dibromo-5,5-dimethylimidazolidine-2,4-dione (2.24 g, 7.83 mmol, 0.53 equiv) at -20 °C in batches.
  • the resulting solution was stirred for 1 h at -20 °C, then quenched by the addition of 30 mL of sat. sodium sulfite (aq).
  • Step B (3R.4R.5RV2-(4-Aminopyrrolor2J-firL2.41triazin-7-ylV3.4-bis(benzyloxyV 5-((benzyloxy)methyl)tetrahvdrofuran-2-ol.
  • Step C (3R,4R,5R)-2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-3,4-bis(benzyloxy)- 5-((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile.
  • Step D (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,l-f][l,2,4]tnazin-7-yl)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-carbonitrile.
  • the title compound may be prepared in a manner analogous to Intermediate 2, Steps A-E, with the modification of replacing DAST with PPh3, CCU, DCE, higher temperature, in Step A.
  • Compound 2 (2 3 4S.5RV2-(4-Aminopyrrolor2J-firi .2.41triazin-7-ylV5-azido-3.4- dihvdroxv-5-(hvdroxvmethvl)tetrahvdrofuran-2-carbonitrile.
  • Step B r2R.3R.4S.5RV2-r4-Aminopyrrolor2.1 -firi.2.41triazin-7-ylV3.4- bis(benzyloxyV5-((benzyloxy ' )methylV5-(fluoromethvntetrahvdrofuran-2-carbonitrile and (2S.3R.4S.5RV2-(4-Aminopyrrolor2J -firL2.41triazin-7-ylV3.4-bis(benzyloxyV5- ((benzyloxy)methyl)-5-(fluoromethyl)tetrahvdrofuran-2-carbonitrile.
  • Step B N-(7-((2R.3R.4SV3.4-Bis((tert-butyldimethylsilvnoxyV2-cvano- 5-methylenetetrahvdrofuran-2-yl)pyrrolo[2,l-f1[l ,2,41triazin-4-yl)benzamide.
  • Step D N-(7-((2 3 4SV3.4-Bis((tert-butyldimethylsilvnoxyV2.5- dicvano-5-(((trimethylsilyl)oxy)methyl)tetrahvdrofuran-2-yl)pyrrolo[2,l-f][l ,2,41triazin-4- vDbenzamide.
  • Step E N-(7-((2 3 4SV2.5-Dicvano-3.4-dihvdroxy-5-(hvdroxymethvn tetrahydrofuran-2-yl)pyrrolo[2, 1 -f
  • Compound 5 Isopropyl ((((2S.3S.4R.5RV5-(4-aminopyrrolor2J-firL2.41triazin-7-ylV5- cvano-2-fluoro-3,4-dihvdroxytetrahvdrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D- alaninate.
  • Step B ((3aS.4S.6R.6aR)-6-(4-AminopyiTolor2J-firi.2.41triazin-7-yl)-6- cvano-4-fluoro-2-methoxytetrahvdrofuro[3,4-dl[l ,31dioxol-4-yl)methyl benzoate.
  • Step C r3aR-4R.6S.6aSV4-r4-Aminopyrrolor2.1-firi.2.41triazin-7-ylV6- fluoro-6-(hvdroxymethylV2-methoxytetrahvdrofuro[3.4-dl [1.31dioxole-4-carbonitrile.
  • Step D Isopropyl ((((3aS.4S.6R.6aR)-6-(4-aminopyrrolor2.1- f
  • Step E Isopropyl ((((2S.3S.4R.5R)-5-(4-aminopyiTolor2.1- f][l,2,41triazin-7-yl)-5-cvano-2-fluoro-3,4-dihvdroxytetrahvdrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-D-alaninate.
  • Step A Isopropyl ((((3aS.4S.6R.6aRV6-(4-aminopyrrolor2.1- f][l ,2,41triazin-7-yl)-6-cvano-4-fluoro-2-methoxytetrahvdrofuro[3,4-dl[l,31dioxol-4- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate.
  • Step B Isopropyl rrrr2S.3S.4R.5RV5-r4-aminopy-Tolor2.l - f
  • EXAMPLE 7 Compound 7: Diisopentyl ((((2S.3S.4R.5RV5-(4-aminopyrrolor2J-firi.2.41triazin-7-ylV5- cvano-2-fluoro-3,4-dihvdroxytetrahvdrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- aspartate.
  • Step A Diisopentyl L-aspartate hydrochloride.
  • L-aspartic acid (1 g, 7.51 mmol) in 3-methylbutan-l-ol (40 mL)
  • chlorotrimethylsilane 5.72 mL, 6.00 equiv
  • the resulting solution was stirred for 48 h at rt.
  • the reaction mixture was concentrated under reduced pressure, the residue was purified on silica gel column with dichloromethane/methanol (50: 1-10: 1) to afford 2.1 g (91%) of the title compound as a yellow oil.
  • Step C Diisopentyl rfff3aS.4S.6R.6aRV6-r4-aminopyrrolor2.l- f
  • Step D Diisopentyl ((((2S.3S.4R.5R)-5-(4-aminopyrrolor2.1- f
  • Compound 8 Neopentyl ((((2S.3S.4R.5RV5-(4-aminopyrrolor2J-firi.2.41triazin-7-vn-5- cvano-2-fluoro-3,4-dihvdroxytetrahvdrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate.
  • Step A 2-Ethylbutyl ((((3aS.4S.6 6aRV6-(4-aminopyrrolor2.1-firL2.41triazin-7- yl)-6-cvano-4-fluoro-2-methoxytetrahydrofuro[3,4-dl[l,31dioxol-4- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate.
  • Step B 2-Ethylbutyl ((((2S.3S.4R.5RV5-(4-aminopyrrolor2J-firL2.41triazin-7-vn-5- cvano-2-fluoro-3,4-dihvdroxytetrahvdrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate.
  • Step A propyl L-alaninate hydrochloride.
  • thionyl chloride 4 g, 33.62 mmol, 6.00 equiv
  • the resulting solution was stirred for 3 h at 90°C, and concentrated under reduced pressure.
  • the resulting solution was diluted with n-hexane.
  • the solids were collected by filtration. This resulted in 900 mg (95%) of propyl L-alaninate hydrochloride as a white solid.
  • Step B dipropyl 2,2'-((chlorophosphoryl)bis(azanediyl))(2S,2'S)-dipropionate.
  • a solution of propyl L-alaninate hydrochloride (855 mg, 6.52 mmol, 2.00 equiv) in dichloromethane (20 mL) under inert atmosphere was added POCh (500 mg, 3.26 mmol, 1.00 equiv) at room temperature.
  • TEA 2.73 mL, 19.56 mmol, 6.00 equiv
  • the resulting solution was stirred for 3 h from -70°C to room temperature.
  • Compound 10 was prepared as follows: A solution of Compound 1 OA (110 mg, 0.17 mmol, 1.00 equiv) in 80% HCOOH/H2O (8 mL) was stirred for 15 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by RP-HPLC (XBridge Prep OBD CI 8 Column, 19x250mm, 5um; mobile phase, A: 0.1% aq.HCOOH, B: 0.1% HCOOH in ACN; gradient 27% to 42.% B in 8 mm; detector, UV 220 nm). This resulted in 31.7 mg (31%) of Compound 10 as a light yellow solid. MS m/z [M+H] + (ESI): 616.
  • Compound 12 ((2S.3S.4R.5RV5-(4-Aminopyrrolor2J-firi.2.41triazin-7-ylV5-cvano-2- fluoro-3,4-dihvdroxytetrahvdrofuran-2-yl)methyl tetrahydrogen triphosphate.
  • tetrabutylammonium salt of pyrophosphate 150 mg was added, followed by DMF (0.5 mL) to get a homogeneous solution. After 1.5 hours at ambient temperature, the reaction was diluted with water (10 mL) and loaded on the column HiLoad 16/10 with Q Sepharose High Performance. Separation was done in a linear gradient of NaCl from 0 to IN in 50 mM TRIS-buffer (pH 7.5). Triphosphate was eluted at 75-80 %B. Corresponding fractions were concentrated. Desalting was achieved by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex).
  • Compound 13 ((2 3S.4 5RV5-(4-Aminopyrrolor2.1-firL2.41triazin-7-ylV5-cvano-2- (fluoromethyl)-3, -dihvdroxytetrahvdrofuran-2-yl)methyl tetrahydrogen triphosphate.
  • Compound 14 r(2R-3S.4R-5RV5-r4-Aminopyrrolor2.1-fi ri.2.41triazin-7-ylV2-azido-5- cvano-3,4-dihvdroxytetrahvdrofuran-2-yl)methyl tetrahydrogen triphosphate.
  • Compound 15 (2R.3R.4S.5RV2-(4-Aminopyrrolor2J-firi.2.41triazin-7-ylV5- (chloromethylV3.4-dihvdroxy-5-(hvdroxymethvntetrahvdrofuran-2-carbonitrile.
  • the title compound may be prepared in a manner analogous to Compound 3, using (3R,4S,5R)-5-(chloromethyl)-3,4-dihydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)- one instead of (3R,4S,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-5-
  • the Dengue virus type 2 strain New Guniea C (NG-C) and the Dengue virus type 4 strain H241 were purchased from ATCC (Manassas, VA; item numbers VR- 1584 and VR-1490, respectively).
  • Huh-7.5 cells were plated in 96 well plates at a density of 1.5 x 10 5 /ml in DMEM medium supplemented with 10% fetal bovine serum, 1% HEPES buffer, 1% Penicillin/Streptomycin and 1% non-essential amino acids (all Mediatech, Manassas, VA).
  • serially diluted compounds were added to cells and incubated for 4 hours.
  • Rhinovirus antiviral assay HRVIB
  • HeLa-OHIO cells (Sigma-Aldrich, St. Louis, MO) were plated in 96 well plates at a density of 1.5 x 10 5 cells per well in assay media (MEM without phenol red or L- glutamine, supplemented with 1% FBS, 1% penicillin/streptomycin, 2 mM GlutaGro, and lx MEM nonessential amino acids, all from Cellgro, Manassas, VA). Assay setup took place after allowing cells to adhere for 24 h. Compounds dissolved in DMSO were serially diluted in assay media to 2x final concentration. Media was aspirated from the cells, and 100 ⁇ media with compound was added in triplicate.
  • Human rhinovirus IB (ATCC, Manassas, VA) was diluted in assay media, and 100 ⁇ was added to cells and compound. The virus inoculum was selected to cause 80-90% cytopathic effect in 4 d. Infected cells were incubated for 4 d at 33°C, 5% CO2. To develop the assay, 100 ⁇ media was replaced with 100 ⁇ CellTiter-Glo® reagent (Promega, Madison, WI), and incubated for 10 mins at RT. Luminescence was measured on a Victor X3 multi-label plate reader. Compounds of Formula (I) showed activity in this HRVIB assay as indicated by the EC50 values provided in Table 6. Compounds of Formula (I) also showed relatively low values of toxicity in the assay as indicated by the CC50 values provided in Table 6.
  • RSV antiviral assay [0309] The HeLa-derived cells containing the stable RSV replicon were cultured in DMEM containing 4500 mg/L D-glucose, L-glutamine, and 110 mg/L sodium pyruvate. The medium was further supplemented with 10% (v/v) FBS (Mediatech), 1% (v/v) penicillin/streptomycin (Mediatech), and 10 ⁇ g/mL of Blasticidin (BSD) (Invivogen). Cells were maintained at 37°C in a humidified 5% CO2 atmosphere. On the first day, 5000 RSV replicon cells per well were plated in a 96-well plate.
  • HEp-2 cells were plated in 96-well plates at the density of 40,000 cells/well.
  • modified vaccinia virus Ankara-T7 (MVA-T7) at the multiplicity of infection of 1 was added to provide T7 RNA polymerase.
  • MVA-T7 modified vaccinia virus Ankara-T7
  • each well was transfected with Lipofectamine2000 (Thermo Fisher) with 0.01 ⁇ g mixture of 6 plasmids including Ebola minigenome, plasmids encoding Ebola L, NP, VP- 35, VP-30 proteins.
  • the human ⁇ -coronavirus strain OC43 was purchased from ATCC (Manassas, VA; item numbers VR-1558 and VR-740, respectively). 24 hours prior to dosing, HeLa human cervix epithelial cells (ATCC, CCL-2) or MRC-5 human lung fibroblast (ATCC, CCL-171) were plated in 96 well plates at a density of 1.5 x 10 5 /ml in DMEM medium supplemented with 10% fetal bovine serum, 1% HEPES buffer, 1% Penicillin/Streptomycin and 1% non-essential amino acids (all Mediatech, Manassas, VA).
  • Compounds of Formula (I) showed activity in this assay against the human ⁇ -coronavirus strain OC43 as indicated by the EC50 values provided in Table 6. Compounds of Formula (I) also showed relatively low values of toxicity in the assay as indicated by the CC50 values provided in Table 6.
  • DENVpol dengue virus NS5 polymerase domain
  • DENVpol assay reactions contained 100 nM recombinant enzyme, 50 nM heteropolymeric RNA, about 0.5 ⁇ tritiated NTP, 0.33 ⁇ of competing cold NTP, 40 mM HEPES (pH 7.5), 3 mM dithiothreitol, and 2 mM MgCk. Standard reactions were incubated for 3 hours at 30°C, in the presence of increasing concentration of inhibitor.
  • HCVpol hepatitis C virus RNA polymerase
  • HRV16pol human rhinovirus 16 RNA polymerase
  • RNA is precipitated with 10% TCA, and acid- insoluble RNA products are filtered on a size exclusion 96-well plate. After washing of the plate, scintillation liquid is added and radiolabeled RNA products are detected according to standard procedures with a Trilux Microbeta scintillation counter.
  • IC50 Trilux Microbeta scintillation counter.
  • the compound concentration at which the enzyme-catalyzed rate is reduced by 50% (IC50) is calculated by fitting the data to a non-linear regression (sigmoidal). Compounds of Formula (I) showed activity in these assays.
  • Standard RSV polymerase assays were conducted in the presence of 3 ⁇ L ⁇ extract of RSV-infected cells in a reaction buffer containing 50 mM tris-acetate pH 8, 120 mM K-acetate, 4.5 mM MgCk, 5% glycerol, 2 mM EDTA, 50 ⁇ BSA, and 3 mM DTT. Varying concentration of NTPs were used to initiate RNA synthesis for 120 minutes at 30 degrees, and radioactive 33P GTP (15 ⁇ ) was used as tracer. The reaction was stopped by adding 50 mM EDTA, and RNA samples were purified through G-50 size exclusion spin columns and phenol-chloroform extraction.
  • RNA products were resolved by electrophoresis on a 6% polyacrylamide TBE gel, and visualized and quantitated after being exposed on a phosphorlmager screen.
  • Polymerase inhibition experiments (IC50s) were conducted the same way in the presence of increasing concentration of NTP analogs. Compounds of Formula (I) showed activity in these assays.

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US20210395288A1 (en) 2021-12-23
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